Chemical compounds

ABSTRACT

There is provided pyrimidinyl compounds of Formula (I), 
     
       
         
         
             
             
         
       
     
     wherein:
         R 2  is       

     
       
         
         
             
             
         
       
     
     or pharmaceutically acceptable salts thereof, processes for their preparation, pharmaceutical compositions containing them and their use in therapy.

The application is a continuation of U.S. application Ser. No.13/540,057, filed Jul. 2, 2012, which is a continuation of U.S.application Ser. No. 13/156,684 (now U.S. Pat. No. 8,252,802), filedJun. 9, 2011, which claims the benefit under 35 U.S.C. §119(e) of U.S.Application No. 61/353,713, filed on Jun. 11, 2010. Each of theseapplications is incorporated by reference in its entirety.

The present invention relates to pyrimidinyl compounds, processes fortheir preparation, pharmaceutical compositions containing them and theiruse in therapy, for example in the treatment of proliferative diseasesuch as cancer and particularly in disease mediated byAtaxia-telangiectasia mutated and RAD-3 related protein kinaseinhibitors, commonly referred to as ATR.

ATR (also known as FRAP-Related Protein 1; FRP1; MEC1; SCKL; SECKL1)protein kinase is a member of the PI3-Kinase like kinase (PIKK) familyof proteins that are involved in repair and maintenance of the genomeand its stability (reviewed in Cimprich K. A. and Cortez D. 2008, NatureRev. Mol. Cell. Biol. 9:616-627). These proteins co-ordinate response toDNA damage, stress and cell-cycle perturbation. Indeed ATM and ATR, twomembers of the family of proteins, share a number of downstreamsubstrates that are themselves recognised components of the cell cycleand DNA-repair machinery e.g. Chk1, BRCA1, p53 (Lakin N D et al, 1999,Oncogene; Tibbets R S et al, 2000, Genes & Dev.). Whilst the substratesof ATM and ATR are to an extent shared, the trigger to activate thesignalling cascade is not shared and ATR primarily responds to stalledreplication forks (Nyberg K. A. et al., 2002, Ann. Rev. Genet.36:617-656; Shechter D. et al. 2004, DNA Repair 3:901-908) and bulky DNAdamage lesions such as those formed by ultraviolet (UV) radiation(Wright J. A. et al, 1998, Proc. Natl. Acad. Sci. USA, 23:7445-7450) orthe UV mimetic agent, 4-nitroquinoline-1-oxide, 4NQO (Ikenaga M. et al.1975, Basic Life Sci. 5b, 763-771). However, double strand breaks (DSB)detected by ATM can be processed into single strand breaks (SSB)recruiting ATR; similarly SSB, detected by ATR can generate DSB,activating ATM. There is therefore a significant interplay between ATMand ATR.

Mutations of the ATR gene that result in complete loss of expression ofthe ATR protein are rare and in general are not viable. Viability mayonly result under heterozygous or hypomorphic conditions. The only clearlink between ATR gene mutations and disease exists in a few patientswith Seckel syndrome which is characterized by growth retardation andmicrocephaly (O'Driscoll M et al, 2003 Nature Genet. Vo13, 497-501).Cells from patients with hypomorphic germline mutations of ATR (seckelsyndrome) present a greater susceptibility to chromosome breakage atfragile sites in presence of replication stress compared to wild typecells (Casper 2004). Disruption of the ATR pathway leads to genomicinstability. Patients with Seckel syndrome also present an increasedincidence of cancer, suggestive of the role of ATR in this disease inthe maintenance of genome stability. Moreover, duplication of the ATRgene has been described as a risk factor in rhabdomyosarcomas (Smith Let al, 1998, Nature Genetics 19, 39-46). Oncogene-driven tumorigenesismay be associated with ATM loss-of-function and therefore increasedreliance on ATR signalling (Gilad 2010). Evidence of replication stresshas also been reported in several tumour types such as colon and ovariancancer, and more recently in glioblastoma, bladder, prostate and breast(Gorgoulis et al., 2005; Bartkova et al. 2005a; Fan et al., 2006; Tortet al., 2006; Nuciforo et al., 2007; Bartkova et al., 2007a). Loss of G1checkpoint is also frequently observed during tumourigenesis. Tumourcells that are deficient in G1 checkpoint controls, in particular p53deficiency, are susceptible to inhibition of ATR activity and presentwith premature chromatin condensation (PCC) and cell death (Ngheim etal, PNAS, 98, 9092-9097).

ATR is essential to the viability of replicating cells and is activatedduring S-phase to regulate firing of replication origins and to repairdamaged replication forks (Shechter D et al, 2004, Nature cell BiologyVol 6 (7) 648-655). Damage to replication forks may arise due toexposure of cells to clinically relevant cytotoxic agents such ashydroxyurea (HU) and platinums (O'Connell and Cimprich 2005; 118, 1-6).ATR is activated by most cancer chemotherapies (Wilsker D et al, 2007,Mol. Cancer. Ther. 6(4) 1406-1413). Biological assessment of the abilityof ATR inhibitors to sensitise to a wide range of chemotherapies havebeen evaluated. Sensitisation of tumour cells to chemotherapeutic agentsin cell growth assays has been noted and used to assess how well weakATR inhibitors (such as Caffeine) will sensitise tumour cell lines tocytotoxic agents. (Wilsker D. et al, 2007, Mol Cancer Ther. 6(4)1406-1413; Sarkaria J. N. et al, 1999, Cancer Res. 59, 4375-4382).Moreover, a reduction of ATR activity by siRNA or ATR knock-in using adominant negative form of ATR in cancer cells has resulted in thesensitisation of tumour cells to the effects of a number of therapeuticor experimental agents such as antimetabolites (5-FU, Gemcitabine,Hydroxyurea, Metotrexate, Tomudex), alkylating agents (Cisplatin,Mitomycin C, Cyclophosphamide, MMS) or double-strand break inducers(Doxorubicin, Ionizing radiation) (Cortez D. et al. 2001, Science,294:1713-1716; Collis S. J. et al, 2003, Cancer Res. 63:1550-1554; ClibyW. A. et al, 1998, EMBO J. 2:159-169) suggesting that the combination ofATR inhibitors with some cytotoxic agents might be therapeuticallybeneficial.

An additional phenotypic assay has been described to define the activityof specific ATR inhibitory compounds is the cell cycle profile (P JHurley, D Wilsker and F Bunz, Oncogene, 2007, 26, 2535-2542). Cellsdeficient in ATR have been shown to have defective cell cycle regulationand distinct characteristic profiles, particularly following a cytotoxiccellular insult. Furthermore, there are proposed to be differentialresponses between tumour and normal tissues in response to modulation ofthe ATR axis and this provides further potential for therapeuticintervention by ATR inhibitor molecules (Rodriguez-Bravo V et al, CancerRes., 2007, 67, 11648-11656).

Another compelling utility of ATR-specific phenotypes is aligned withthe concept of synthetic lethality and the observation that tumour cellsthat are deficient in G1 checkpoint controls, in particular p53deficiency, are susceptible to inhibition of ATR activity resulting inpremature chromatin condensation (PCC) and cell death (Ngheim et al,PNAS, 98, 9092-9097). In this situation, S-phase replication of DNAoccurs but is not completed prior to M-phase initiation due to failurein the intervening checkpoints resulting in cell death from a lack ofATR signalling. The G2/M checkpoint is a key regulatory controlinvolving ATR (Brown E. J. and Baltimore D., 2003, Genes Dev. 17,615-628) and it is the compromise of this checkpoint and the preventionof ATR signalling to its downstream partners which results in PCC.Consequently, the genome of the daughter cells is compromised andviability of the cells is lost (Ngheim et al, PNAS, 98, 9092-9097).

It has thus been proposed that inhibition of ATR may prove to be anefficacious approach to future cancer therapy (Collins I. and Garret M.D., 2005, Curr. Opin. Pharmacol., 5:366-373; Kaelin W. G. 2005, NatureRev. Cancer, 5:689-698) in the appropriate genetic context such astumours with defects in ATM function or other S-phase checkpoints. Untilrecently, There is currently no clinical precedent for agents targetingATR, although agents targeting the downstream signalling axis i.e. Chk1are currently undergoing clinical evaluation (reviewed in Janetka J. W.et al. Curr Opin Drug Discov Devel, 2007, 10:473-486). However,inhibitors targeting ATR kinase have recently been described (Reaper2011, Charrier 2011).

In summary ATR inhibitors have the potential to sensitise tumour cellsto ionising radiation or DNA-damage inducing chemotherapeutic agents,have the potential to induce selective tumour cell killing as well as toinduce synthetic lethality in subsets of tumour cells with defects inDNA damage response.

In accordance with a first aspect of the present invention, there isprovided a compound of formula (I):

wherein:

R¹ is selected from morpholin-4-yl and 3-methylmorpholin-4-yl;

R² is

n is 0 or 1;

R^(2A), R^(2C), R^(2E) and R^(2F) each independently are hydrogen ormethyl;

R^(2B) and R^(2D) each independently are hydrogen or methyl;

R^(2G) is selected from —NHR⁷ and —NHCOR⁸;

R^(2H) is fluoro;

R³ is methyl;

R⁴ and R⁵ are each independently hydrogen or methyl, or R⁴ and R⁵together with the atom to which they are attached form Ring A;

Ring A is a C₃₋₆cycloalkyl or a saturated 4-6 membered heterocyclic ringcontaining one heteroatom selected from O and N;

R⁶ is hydrogen;

R⁷ is hydrogen or methyl;

R⁸ is methyl,

or a pharmaceutically acceptable salt thereof.

In accordance with a first aspect of the present invention, there isprovided a compound of formula (I):

wherein:

R¹ is 3-methylmorpholin-4-yl;

R² is

n is 0 or 1;

R^(2A), R^(2C), R^(2E) and R^(2F) each independently are hydrogen ormethyl;

R^(2B) and R^(2D) each independently are hydrogen or methyl;

R^(2G) is selected from —NH₂, —NHMe and —NHCOMe;

R^(2H) is fluoro;

R³ is methyl;

R⁴ and R⁵ are each independently hydrogen or methyl, or R⁴ and R⁵together with the atom to which they are attached form Ring A;

Ring A is a C₃₋₆cycloalkyl or a saturated 4-6 membered heterocyclic ringcontaining one heteroatom selected from O and N; and

R⁶ is hydrogen,

or a pharmaceutically acceptable salt thereof.

Certain compounds of formula (I) are capable of existing instereoisomeric forms. It will be understood that the inventionencompasses all geometric and optical isomers of the compounds offormula (I) and mixtures thereof including racemates. Tautomers andmixtures thereof also form an aspect of the present invention. Solvatesand mixtures thereof also form an aspect of the present invention. Forexample, a suitable solvate of a compound of formula (I) is, forexample, a hydrate such as a hemi-hydrate, a mono-hydrate, a di-hydrateor a tri-hydrate or an alternative quantity thereof.

FIG. 1: Shows the Perspective view of the molecular structure of Example2.02 obtained from crystals that were grown and isolated by slowevaporation to dryness in air from EtOAc. The asymmetric unit containstwo crystallographically unique molecules.

It is to be understood that, insofar as certain of the compounds offormula (I) defined above may exist in optically active or racemic formsby virtue of one or more asymmetric carbon atoms or sulphur atoms, theinvention includes in its definition any such optically active orracemic form which possesses the above-mentioned activity. The presentinvention encompasses all such stereoisomers having activity as hereindefined. It is further to be understood that in the names of chiralcompounds (R,S) denotes any scalemic or racemic mixture while (R) and(S) denote the enantiomers. In the absence of (R,S), (R) or (S) in thename it is to be understood that the name refers to any scalemic orracemic mixture, wherein a scalemic mixture contains R and S enantiomersin any relative proportions and a racemic mixture contains R and Senantiomers in the ratio 50:50. The synthesis of optically active formsmay be carried out by standard techniques of organic chemistry wellknown in the art, for example by synthesis from optically activestarting materials or by resolution of a racemic form. Racemates may beseparated into individual enantiomers using known procedures (see, forexample, Advanced Organic Chemistry: 3rd Edition: author J March, p104-107). A suitable procedure involves formation of diastereomericderivatives by reaction of the racemic material with a chiral auxiliary,followed by separation, for example by chromatography, of thediastereomers and then cleavage of the auxiliary species. Similarly, theabove-mentioned activity may be evaluated using the standard laboratorytechniques referred to hereinafter.

It will be understood that the invention encompasses compounds with oneor more isotopic substitutions. For example, H may be in any isotopicform, including ¹H, ²H (D), and ³H (T); C may be in any isotopic form,including ¹²C, ¹³C, and ¹⁴C; O may be in any isotopic form, including¹⁶O and ¹⁸O; and the like.

The present invention relates to the compounds of formula (I) as hereindefined as well as to salts thereof. Salts for use in pharmaceuticalcompositions will be pharmaceutically acceptable salts, but other saltsmay be useful in the production of the compounds of formula (I) andtheir pharmaceutically acceptable salts. Pharmaceutically acceptablesalts of the invention may, for example, include acid addition salts ofcompounds of formula (I) as herein defined which are sufficiently basicto form such salts. Such acid addition salts include but are not limitedto furmarate, methanesulfonate, hydrochloride, hydrobromide, citrate andmaleate salts and salts formed with phosphoric and sulfuric acid. Inaddition where compounds of formula (I) are sufficiently acidic, saltsare base salts and examples include but are not limited to, an alkalimetal salt for example sodium or potassium, an alkaline earth metal saltfor example calcium or magnesium, or organic amine salt for exampletriethylamine, ethanolamine, diethanolamine, triethanolamine,morpholine, N-methylpiperidine, N-ethylpiperidine, dibenzylamine oramino acids such as lysine.

The compounds of formula (I) may also be provided as in vivohydrolysable esters. An in vivo hydrolysable ester of a compound offormula (I) containing carboxy or hydroxy group is, for example apharmaceutically acceptable ester which is cleaved in the human oranimal body to produce the parent acid or alcohol. Such esters can beidentified by administering, for example, intravenously to a testanimal, the compound under test and subsequently examining the testanimal's body fluid.

Suitable pharmaceutically acceptable esters for carboxy includeC₁₋₆alkoxymethyl esters for example methoxymethyl, C₁₋₆alkanoyloxymethylesters for example pivaloyloxymethyl, phthalidyl esters,C₃₋₈cycloalkoxycarbonyloxyC₁₋₆alkyl esters for example1-cyclohexylcarbonyloxyethyl, 1,3-dioxolen-2-onylmethyl esters forexample 5-methyl-1,3-dioxolen-2-onylmethyl, andC₁₋₆alkoxycarbonyloxyethyl esters for example 1-methoxycarbonyloxyethyl;and may be formed at any carboxy group in the compounds of thisinvention.

Suitable pharmaceutically acceptable esters for hydroxy includeinorganic esters such as phosphate esters (including phosphoramidiccyclic esters) and α-acyloxyalkyl ethers and related compounds which asa result of the in vivo hydrolysis of the ester breakdown to give theparent hydroxy group/s. Examples of α-acyloxyalkyl ethers includeacetoxymethoxy and 2,2-dimethylpropionyloxymethoxy. A selection of invivo hydrolysable ester forming groups for hydroxy includeC₁₋₁₀alkanoyl, for example formyl, acetyl, benzoyl, phenylacetyl,substituted benzoyl and phenylacetyl; C₁₋₁₀alkoxycarbonyl (to give alkylcarbonate esters), for example ethoxycarbonyl; di-C₁₋₄alkylcarbamoyl andN-(di-C₁₋₄alkylaminoethyl)-N—C₁₋₄alkylcarbamoyl (to give carbamates);di-C₁₋₄alkylaminoacetyl and carboxyacetyl. Examples of ring substituentson phenylacetyl and benzoyl include aminomethyl, C₁₋₄alkylaminomethyland di-(C₁₋₄alkyl)aminomethyl, and morpholino or piperazino linked froma ring nitrogen atom via a methylene linking group to the 3- or4-position of the benzoyl ring. Other interesting in vivo hydrolysableesters include, for example, R^(A)C(O)OC₁₋₆alkyl-CO—, wherein R^(A) isfor example, benzyloxy-C₁₋₄alkyl, or phenyl. Suitable substituents on aphenyl group in such esters include, for example,4-C₁₋₄piperazino-C₁₋₄alkyl, piperazino-C₁₋₄alkyl andmorpholino-C₁₋₄alkyl.

The compounds of the formula (I) may be also be administered in the formof a prodrug which is broken down in the human or animal body to give acompound of the formula (I). Various forms of prodrugs are known in theart. For examples of such prodrug derivatives, see:

a) Design of Prodrugs, edited by H. Bundgaard, (Elsevier, 1985) andMethods in Enzymology, Vol. 42, p. 309-396, edited by K. Widder, et al.(Academic Press, 1985);b) A Textbook of Drug Design and Development, edited byKrogsgaard-Larsen and H. Bundgaard, Chapter 5 “Design and Application ofProdrugs”, by H. Bundgaard p. 113-191 (1991);

c) H. Bundgaard, Advanced Drug Delivery Reviews, 8, 1-38 (1992); d) H.Bundgaard, et al., Journal of Pharmaceutical Sciences, 77, 285 (1988);and e) N. Kakeya, et al., Chem Pharm Bull, 32, 692 (1984).

In this specification the generic term “C_(p-q)alkyl” includes bothstraight-chain and branched-chain alkyl groups. However references toindividual alkyl groups such as “propyl” are specific for the straightchain version only (i.e. n-propyl and isopropyl) and references toindividual branched-chain alkyl groups such as “tert-butyl” are specificfor the branched chain version only.

The prefix C_(p-q) in C_(p-q)alkyl and other terms (where p and q areintegers) indicates the range of carbon atoms that are present in thegroup, for example C₁₋₄alkyl includes C₁alkyl (methyl), C₂alkyl (ethyl),C₃alkyl (propyl as n-propyl and isopropyl) and C₄alkyl (n-butyl,sec-butyl, isobutyl and tert-butyl).

The term C_(p-q)alkoxy comprises —O—C_(p-q)alkyl groups.

The term C_(p-q)alkanoyl comprises —C(O)alkyl groups.

The term halo includes fluoro, chloro, bromo and iodo.

“Carbocyclyl” is a saturated, unsaturated or partially saturatedmonocyclic ring system containing from 3 to 6 ring atoms, wherein a ringCH₂ group may be replaced with a C═O group. “Carbocyclyl” includes“aryl”, “C_(p-q)cycloalkyl” and “C_(p-q)cycloalkenyl”.

“aryl” is an aromatic monocyclic carbocyclyl ring system.

“C_(p-q)cycloalkenyl” is an unsaturated or partially saturatedmonocyclic carbocyclyl ring system containing at least 1 C═C bond andwherein a ring CH₂ group may be replaced with a C═O group.

“C_(p-q)cycloalkyl” is a saturated monocyclic carbocyclyl ring systemand wherein a ring CH₂ group may be replaced with a C═O group.

“Heterocyclyl” is a saturated, unsaturated or partially saturatedmonocyclic ring system containing from 3 to 6 ring atoms of which 1, 2or 3 ring atoms are chosen from nitrogen, sulfur or oxygen, which ringmay be carbon or nitrogen linked and wherein a ring nitrogen or sulfuratom may be oxidised and wherein a ring CH₂ group may be replaced with aC═O group. “Heterocyclyl” includes “heteroaryl”, “cycloheteroalkyl” and“cycloheteroalkenyl”.

“Heteroaryl” is an aromatic monocyclic heterocyclyl, particularly having5 or 6 ring atoms, of which 1, 2 or 3 ring atoms are chosen fromnitrogen, sulfur or oxygen where a ring nitrogen or sulfur may beoxidised.

“Cycloheteroalkenyl” is an unsaturated or partially saturated monocyclicheterocyclyl ring system, particularly having 5 or 6 ring atoms, ofwhich 1, 2 or 3 ring atoms are chosen from nitrogen, sulfur or oxygen,which ring may be carbon or nitrogen linked and wherein a ring nitrogenor sulfur atom may be oxidised and wherein a ring CH₂ group may bereplaced with a C═O group.

“Cycloheteroalkyl” is a saturated monocyclic heterocyclic ring system,particularly having 5 or 6 ring atoms, of which 1, 2 or 3 ring atoms arechosen from nitrogen, sulfur or oxygen, which ring may be carbon ornitrogen linked and wherein a ring nitrogen or sulfur atom may beoxidised and wherein a ring CH₂ group may be replaced with a C═O group.

This specification may make use of composite terms to describe groupscomprising more than one functionality. Unless otherwise describedherein, such terms are to be interpreted as is understood in the art.For example carbocyclylC_(p-q)alkyl comprises C_(p-q)alkyl substitutedby carbocyclyl, heterocyclylC_(p-q)alkyl comprises C_(p-q)alkylsubstituted by heterocyclyl, and bis(C_(p-q)alkyl)amino comprises aminosubstituted by 2 C_(p-q)alkyl groups which may be the same or different.

HaloC_(p-q)alkyl is a C_(p-q)alkyl group that is substituted by 1 ormore halo substituents and particularly 1, 2 or 3 halo substituents.Similarly, other generic terms containing halo such as haloC_(p-q)alkoxymay contain 1 or more halo substituents and particularly 1, 2 or 3 halosubstituents.

HydroxyC_(p-q)alkyl is a C_(p-q)alkyl group that is substituted by 1 ormore hydroxyl substituents and particularly by 1, 2 or 3 hydroxysubstituents. Similarly other generic terms containing hydroxy such ashydroxyC_(p-q)alkoxy may contain 1 or more and particularly 1, 2 or 3hydroxy substituents.

C_(p-q)alkoxyC_(p-q)alkyl is a C_(p-q)alkyl group that is substituted by1 or more C_(p-q)alkoxy substituents and particularly 1, 2 or 3C_(p-q)alkoxy substituents. Similarly other generic terms containingC_(p-q)alkoxy such as C_(p-q)alkoxyC_(p-q)alkoxy may contain 1 or moreC_(p-q)alkoxy substituents and particularly 1, 2 or 3 C_(p-q)alkoxysubstituents.

Where optional substituents are chosen from “1 or 2”, from “1, 2, or 3”or from “1, 2, 3 or 4” groups or substituents it is to be understoodthat this definition includes all substituents being chosen from one ofthe specified groups i.e. all substitutents being the same or thesubstituents being chosen from two or more of the specified groups i.e.the substitutents not being the same.

Compounds of the present invention have been named with the aid ofcomputer software (ACD/Name version 10.06).

“Proliferative disease(s)” includes malignant disease(s) such as canceras well as non-malignant disease(s) such as inflammatory diseases,obstracutive airways diseases, immune diseases or cardiovasculardiseases.

Suitable values for any R group or any part or substitutent for suchgroups include:

-   for C₁₋₃alkyl: methyl, ethyl, propyl and iso-propyl;-   for C₁₋₆alkyl: C₁₋₃alkyl, butyl, 2-methylpropyl, tert-butyl, pentyl,    2,2-dimethylpropyl, 3-methylbutyl and hexyl;-   for C₃₋₆cycloalkyl: cyclopropyl, cyclobutyl, cyclopentyl and    cyclohexyl;-   for C₃₋₆cycloalkylC₁₋₃alkyl: cyclopropylmethyl, cyclopropylethyl,    cyclobutylmethyl, cyclopentylmethyl and cyclohexylmethyl;-   for aryl: phenyl;-   for arylC₁₋₃alkyl: benzyl and phenethyl;-   for carbocylyl: aryl, cyclohexenyl and C₃₋₆cycloalkyl;-   for halo: fluoro, chloro, bromo and iodo;-   for C₁₋₃alkoxy: methoxy, ethoxy, propoxy and isopropoxy;-   for C₁₋₆alkoxy: C₁₋₃alkoxy, butoxy, tert-butoxy, pentyloxy,    1-ethylpropoxy and hexyloxy;-   for C₁₋₃alkanoyl: acetyl and propanoyl;-   for C₁₋₆alkanoyl: acetyl, propanoyl and 2-methylpropanoyl;-   for heteroaryl: pyridinyl, imidazolyl, pyrimidinyl, thienyl,    pyrrolyl, pyrazolyl, thiazolyl, thiazolyl, triazolyl, oxazolyl,    isoxazolyl, furanyl, pyridazinyl and pyrazinyl;-   for heteroarylC₁₋₃alkyl: pyrrolylmethyl, pyrrolylethyl,    imidazolylmethyl, imidazolylethyl, pyrazolylmethyl, pyrazolylethyl,    furanylmethyl, furanylethyl, thienylmethyl, theinylethyl,    pyridinylmethyl, pyridinylethyl, pyrazinylmethyl, pyrazinylethyl,    pyrimidinylmethyl, pyrimidinylethyl, pyrimidinylpropyl,    pyrimidinylbutyl, imidazolylpropyl, imidazolylbutyl,    1,3,4-triazolylpropyl and oxazolylmethyl;-   for heterocyclyl: heteroaryl, pyrrolidinyl, piperidinyl,    piperazinyl, azetidinyl, morpholinyl, dihydro-2H-pyranyl,    tetrahydropyridine and tetrahydrofuranyl;-   for saturated heterocyclyl: oxetanyl, pyrrolidinyl, piperidinyl,    piperazinyl, azetidinyl, morpholinyl, tetrahydropyranyl and    tetrahydrofuranyl.

It should be noted that examples given for terms used in the descriptionare not limiting.

Particular values of Ring A, n, R¹, R², R⁴, R⁵, R⁶, R⁷ and R⁸ are asfollows. Such values may be used individually or in combination whereappropriate, in connection with any aspect of the invention, or partthereof, and with any of the definitions, claims or embodiments definedherein.

n

In one aspect n is 0.

In another aspect n is 1.

R¹

In one aspect, R¹ is selected from morpholin-4-yl and3-methylmorpholin-4-yl.

In a further aspect, R¹ is 3-methylmorpholin-4-yl.

In a further aspect, R¹ is

In a further aspect, R¹ is

R²

In one aspect R² is

In one aspect R² is

In one aspect R² is

In one aspect R² is

R^(2A)

R^(2A) is hydrogen.

R^(2B)

R^(2B) is hydrogen.

R^(2C)

R^(2C) is hydrogen.

R^(2D)

R^(2D) is hydrogen.

R^(2E)

R^(2E) is hydrogen.

R^(2F)

R^(2F) is hydrogen.

R^(2G)

In one aspect of the invention R^(2G) is selected from —NHR⁷ and—NHCOR⁸.

In one aspect of the invention R^(2G) is —NHR⁷.

In one aspect of the invention R^(2G) is —NHCOR⁸.

In one aspect of the invention R^(2G) is selected from —NH₂, —NHMe and—NHCOMe.

In one aspect of the invention R^(2G) is —NH₂.

In one aspect of the invention R^(2G) is —NHMe.

In one aspect of the invention R^(2G) is —NHCOMe.

R⁴ and R⁵

In one aspect of the invention R⁴ and R⁵ are hydrogen.

In one aspect of the invention R⁴ and R⁵ are methyl.

In one aspect of the invention R⁴ and R⁵ together with the atom to whichthey are attached form Ring A.

Ring A

In one aspect of the invention Ring A is a C₃₋₆cycloalkyl or a saturated4-6 heterocyclic ring containing one heteroatom selected from O and N

In another aspect Ring A is a cyclopropyl, cyclobutyl, cyclopentyl,oxetanyl, tetrahydrofuryl, tetrahydropyranyl, azetidinyl, pyrrolidinylor piperidinyl ring.

In another aspect Ring A is a cyclopropyl, cyclobutyl, cylopentyl,tetrahydropyranyl or piperidinyl ring.

In another aspect Ring A is a cyclopropyl, cylopentyl, tetrahydropyranylor piperidinyl ring.

In another aspect Ring A is a cyclopropyl, tetrahydropyranyl orpiperidinyl ring.

In another aspect Ring A is a cyclopropyl or tetrahydropyranyl ring.

In another aspect Ring A is a piperidinyl ring.

In another aspect Ring A is a tetrahydropyranyl ring.

In another aspect Ring A is a cyclopropyl ring.

R⁶

In one aspect R⁶ is hydrogen.

R⁷

In one aspect R⁷ is hydrogen or methyl.

In one aspect R⁷ is methyl.

In one aspect R⁷ is hydrogen.

R⁸

In one aspect R¹² is methyl.

In one aspect of the invention there is provided a subset of compoundsof formula (I), or a pharmaceutically acceptable salt thereof;

R¹ is selected from morpholin-4-yl and 3-methylmorpholin-4-yl;

n is 0 or 1;

R^(2A) is hydrogen;

R^(2B) is hydrogen;

R^(2C) is hydrogen;

R^(2D) is hydrogen;

R^(2E) is hydrogen;

R^(2F) is hydrogen;

R^(2G) is selected from —NHR⁷ and —NHCOR⁸;

R^(2H) is fluoro;

R³ is methyl;

R⁴ and R⁵ together with the atom to which they are attached form Ring A;

Ring A is a C₃₋₆cycloalkyl or a saturated 4-6 heterocyclic ringcontaining one heteroatom selected from O and N;

R⁶ is hydrogen;

R⁷ is hydrogen or methyl; and

R⁸ is methyl.

In another aspect of the invention there is provided a subset ofcompounds of formula (I), or a pharmaceutically acceptable salt thereof;

R¹ is selected from morpholin-4-yl and 3-methylmorpholin-4-yl;

n is 0 or 1;

R^(2A) is hydrogen;

R^(2B) is hydrogen;

R^(2C) is hydrogen;

R^(2D) is hydrogen;

R^(2E) is hydrogen;

R^(2F) is hydrogen;

R^(2G) is selected from —NH₂, —NHMe and —NHCOMe;

R^(2H) is fluoro;

R³ is methyl;

R⁴ and R⁵ together with the atom to which they are attached form Ring A;

Ring A is a C₃₋₆cycloalkyl or a saturated 4-6 heterocyclic ringcontaining one heteroatom selected from O and N; and

R⁶ is hydrogen.

In another aspect of the invention there is provided a subset ofcompounds of formula (I), or a pharmaceutically acceptable salt thereof;

R¹ is selected from morpholin-4-yl and 3-methylmorpholin-4-yl;

n is 0 or 1;

R^(2A) is hydrogen;

R^(2B) is hydrogen;

R^(2C) is hydrogen;

R^(2D) is hydrogen;

R^(2E) is hydrogen;

R^(2F) is hydrogen;

R^(2G) is selected from —NHR⁷ and —NHCOR⁸;

R^(2H) is fluoro;

R³ is methyl;

R⁴ and R⁵ together with the atom to which they are attached form Ring A;

Ring A is a cyclopropyl, cyclobutyl, cyclopentyl, oxetanyl,tetrahydrofuryl, tetrahydropyranyl, azetidinyl, pyrrolidinyl orpiperidinyl ring;

R⁶ is hydrogen;

R⁷ is hydrogen or methyl; and

R⁸ is methyl.

In another aspect of the invention there is provided a subset ofcompounds of formula (I), or a pharmaceutically acceptable salt thereof;

R¹ is selected from morpholin-4-yl and 3-methylmorpholin-4-yl;

n is 0 or 1;

R^(2A) is hydrogen;

R^(2B) is hydrogen;

R² is hydrogen;

R^(2D) is hydrogen;

R^(2E) is hydrogen;

R^(2F) is hydrogen;

R^(2G) is selected from —NH₂, —NHMe and —NHCOMe;

R^(2H) is fluoro;

R³ is methyl;

R⁴ and R⁵ together with the atom to which they are attached form Ring A;

Ring A is a cyclopropyl, cyclobutyl, cyclopentyl, oxetanyl,tetrahydrofuryl, tetrahydropyranyl, azetidinyl, pyrrolidinyl orpiperidinyl ring; and

R⁶ is hydrogen.

In another aspect of the invention there is provided a subset ofcompounds of formula (Ia),

or a pharmaceutically acceptable salt thereof;

Ring A is a cyclopropyl, tetrahydropyranyl or piperidinyl ring;

R² is

n is 0 or 1;

R^(2A) is hydrogen;

R^(2B) is hydrogen;

R^(2C) is hydrogen;

R^(2D) is hydrogen;

R^(2E) is hydrogen;

R^(2F) is hydrogen;

R^(2G) is selected from —NHR⁷ and —NHCOR⁸;

R^(2H) is fluoro;

R³ is a methyl group;

R⁶ is hydrogen;

R⁷ is hydrogen or methyl; and

R⁸ is methyl.

In another aspect of the invention there is provided a subset ofcompounds of formula (Ia),

or a pharmaceutically acceptable salt thereof;

Ring A is a cyclopropyl, tetrahydropyranyl or piperidinyl ring;

R² is

n is 0 or 1;

R^(2A) is hydrogen;

R^(2B) is hydrogen;

R^(2C) is hydrogen;

R^(2D) is hydrogen;

R^(2E) is hydrogen;

R^(2F) is hydrogen;

R^(2G) is selected from —NH₂, —NHMe and —NHCOMe;

R^(2H) is fluoro;

R³ is a methyl group; and

R⁶ is hydrogen.

In another aspect of the invention there is provided a subset ofcompounds of formula (Ia),

or a pharmaceutically acceptable salt thereof;

Ring A is a cyclopropyl, tetrahydropyranyl or piperidinyl ring;

R² is

n is 0 or 1;

R^(2A) is hydrogen;

R^(2B) is hydrogen;

R^(2C) is hydrogen;

R^(2D) is hydrogen;

R^(2E) is hydrogen;

R^(2F) is hydrogen;

R^(2G) is —NHR⁷;

R^(2H) is fluoro;

R³ is a methyl group;

R⁶ is hydrogen; and

R⁷ is hydrogen.

In another aspect of the invention there is provided a subset ofcompounds of formula (Ia),

or a pharmaceutically acceptable salt thereof;

Ring A is a cyclopropyl ring;

R² is

n is 0;

R^(2A) is hydrogen;

R^(2B) is hydrogen;

R^(2C) is hydrogen;

R^(2D) is hydrogen;

R^(2E) is hydrogen;

R^(2F) is hydrogen;

R^(2G) is —NHR⁷;

R^(2H) is fluoro;

R³ is a methyl group;

R⁶ is hydrogen; and

R⁷ is methyl.

In another aspect of the invention provides a compound, or a combinationof compounds, selected from any one of the Examples or apharmaceutically acceptable salt thereof.

In another aspect of the invention there is provided a compound, or acombination of compounds, selected from any one of

-   4-{4-[(3R)-3-Methylmorpholin-4-yl]-6-[((R)—S-methylsulfonimidoyl)methyl]pyrimidin-2-yl}-1H-pyrrolo[2,3-b]pyridine;-   4-{4-[(3R)-3-Methylmorpholin-4-yl]-6-[1-((S)—S-methylsulfonimidoyl)cyclopropyl]pyrimidin-2-yl}-1H-pyrrolo[2,3-b]pyridine;-   4-{4-[(3R)-3-Methylmorpholin-4-yl]-6-[1-((R)—S-methylsulfonimidoyl)cyclopropyl]pyrimidin-2-yl}-1H-pyrrolo[2,3-b]pyridine;-   N-Methyl-1-{4-[(3R)-3-methylmorpholin-4-yl]-6-[1-((R)—S-methylsulfonimidoyl)cyclopropyl]pyrimidin-2-yl}-1H-benzimidazol-2-amine;-   N-Methyl-1-{4-[(3R)-3-methylmorpholin-4-yl]-6-[1-((S)—S-methylsulfonimidoyl)cyclopropyl]pyrimidin-2-yl}-1H-benzimidazol-2-amine;-   4-{4-[(3R)-3-Methylmorpholin-4-yl]-6-[1-((R)—S-methylsulfonimidoyl)cyclopropyl]pyrimidin-2-yl}-1H-indole;-   4-{4-[(3R)-3-methylmorpholin-4-yl]-6-[1-((S)—S-methylsulfonimidoyl)cyclopropyl]pyrimidin-2-yl}-1H-indole;-   1-{4-[(3R)-3-Methylmorpholin-4-yl]-6-[1-((R)—S-methylsulfonimidoyl)cyclopropyl]pyrimidin-2-yl}-1H-benzimidazol-2-amine;-   1-{4-[(3R)-3-methylmorpholin-4-yl]-6-[1-((S)—S-methylsulfonimidoyl)cyclopropyl]pyrimidin-2-yl}-1H-benzimidazol-2-amine;-   4-Fluoro-N-methyl-1-{4-[(3R)-3-methylmorpholin-4-yl]-6-[1-((R)—S-methylsulfonimidoyl)cyclopropyl]pyrimidin-2-yl}-1H-benzimidazol-2-amine;-   4-fluoro-N-methyl-1-{4-[(3R)-3-methylmorpholin-4-yl]-6-[1-((S)—S-methylsulfonimidoyl)cyclopropyl]pyrimidin-2-yl}-1H-benzimidazol-2-amine;-   4-{4-[(3R)-3-Methylmorpholin-4-yl]-6-[1-(S-methylsulfonimidoyl)cyclopropyl]pyrimidin-2-yl}-1H-pyrrolo[2,3-c]pyridine;-   N-methyl-1-{4-[1-methyl-1-((S)—S-methylsulfonimidoyl)ethyl]-6-[(3R)-3-methylmorpholin-4-yl]pyrimidin-2-yl}-1H-benzimidazol-2-amine;-   N-methyl-1-{4-[1-methyl-1-((R)—S-methylsulfonimidoyl)ethyl]-6-[(3R)-3-methylmorpholin-4-yl]pyrimidin-2-yl}-1H-benzimidazol-2-amine;-   N-Methyl-1-{4-[(3R)-3-methylmorpholin-4-yl]-6-[4-((S)—S-methylsulfonimidoyl)tetrahydro-2H-pyran-4-yl]pyrimidin-2-yl}-1H-benzimidazol-2-amine;-   N-methyl-1-{4-[(3R)-3-methylmorpholin-4-yl]-6-[4-((R)—S-methylsulfonimidoyl)tetrahydro-2H-pyran-4-yl]pyrimidin-2-yl}-1H-benzimidazol-2-amine;-   4-{4-[(3R)-3-Methylmorpholin-4-yl]-6-[4-((S)—S-methylsulfonimidoyl)tetrahydro-2H-pyran-4-yl]pyrimidin-2-yl}-1H-indole;-   4-Fluoro-N-methyl-1-{4-[1-methyl-1-((S)—S-methylsulfonimidoyl)ethyl]-6-[(3R)-3-methylmorpholin-4-yl]pyrimidin-2-yl}-1H-benzimidazol-2-amine;-   4-fluoro-N-methyl-1-{4-[1-methyl-1-((R)—S-methylsulfonimidoyl)ethyl]-6-[(3R)-3-methylmorpholin-4-yl]pyrimidin-2-yl}-1H-benzimidazol-2-amine;-   6-Fluoro-N-methyl-1-{4-[1-methyl-1-((R)—S-methylsulfonimidoyl)ethyl]-6-[(3R)-3-methylmorpholin-4-yl]pyrimidin-2-yl}-1H-benzimidazol-2-amine;-   5-Fluoro-N-methyl-1-{4-[1-methyl-1-((R)—S-methylsulfonimidoyl)ethyl]-6-[(3R)-3-methylmorpholin-4-yl]pyrimidin-2-yl}-1H-benzimidazol-2-amine;-   5-Fluoro-N-methyl-1-{4-[1-methyl-1-((S)—S-methylsulfonimidoyl)ethyl]-6-[(3R)-3-methylmorpholin-4-yl]pyrimidin-2-yl}-1H-benzimidazol-2-amine;-   6-fluoro-N-methyl-1-{4-[1-methyl-1-((S)—S-methylsulfonimidoyl)ethyl]-6-[(3R)-3-methylmorpholin-4-yl]pyrimidin-2-yl}-1H-benzimidazol-2-amine;-   6-Fluoro-N-methyl-1-{4-[(3R)-3-methylmorpholin-4-yl]-6-[1-((R)—S-methylsulfonimidoyl)cyclopropyl]pyrimidin-2-yl}-1H-benzimidazol-2-amine;-   5-fluoro-N-methyl-1-{4-[(3R)-3-methylmorpholin-4-yl]-6-[1-((R)—S-methylsulfonimidoyl)cyclopropyl]pyrimidin-2-yl}-1H-benzimidazol-2-amine;-   5-fluoro-N-methyl-1-{4-[(3R)-3-methylmorpholin-4-yl]-6-[1-((S)—S-methylsulfonimidoyl)cyclopropyl]pyrimidin-2-yl}-1H-benzimidazol-2-amine;    and-   6-fluoro-N-methyl-1-{4-[(3R)-3-methylmorpholin-4-yl]-6-[1-((S)—S-methylsulfonimidoyl)cyclopropyl]pyrimidin-2-yl}-1H-benzimidazol-2-amine,    or a pharmaceutically acceptable salt thereof.

In another aspect of the invention there is provided a compound, or acombination of compounds, selected from any one of

-   4-{4-[(3R)-3-methylmorpholin-4-yl]-6-[(R)—(S-methylsulfonimidoyl)methyl]pyrimidin-2-yl}-1H-pyrrolo[2,3-b]pyridine;-   4-{4-[(3R)-3-methylmorpholin-4-yl][1-((S)—S-methylsulfonimidoyl)cyclopropyl]pyrimidin-2-yl}-1H-pyrrolo[2,3-b]pyridine;-   4-{4-[(3R)-3-methylmorpholin-4-yl]-6-[1-((R)—S-methylsulfonimidoyl)cyclopropyl]pyrimidin-2-yl}-1H-pyrrolo[2,3-b]pyridine;-   N-methyl-1-{4-[(3R)-3-methylmorpholin-4-yl]-6-[1-(R)—(S-methylsulfonimidoyl)cyclopropyl]pyrimidin-2-yl}-1H-benzimidazol-2-amine;    and-   N-methyl-1-{4-[(3R)-3-methylmorpholin-4-yl]-6-[1-(S)—(S-methylsulfonimidoyl)cyclopropyl]pyrimidin-2-yl}-1H-benzimidazol-2-amine,    or a pharmaceutically acceptable salt thereof.

A compound of formula (I) may be prepared from a compound of formula(II), wherein L² is a leaving group (such as halo or —SMe, etc.), byreaction with a compound of formula (IIIa), (IIIb) or (IIIc), wherein Xis a suitable group (such as boronic acid or ester) in the presence of asuitable Pd catalyst and phosphine ligand in a suitable solvent such asa mixture of N,N-dimethylformamide, dimethoxyethane, water and ethanol,under suitable conditions such as heating in a microwave reactor.Alternatively, a compound of formula (I) may be prepared from a compoundof formula (II), wherein L² is a leaving group (such as halo or —SMe,etc.), by reaction with a compound of formula (IIId), with a suitablebase such as NaH, Na₂CO₃, Cs₂CO₃ or K₂CO₃ in a suitable solvent such asN,N-dimethylformamide or N,N-dimethylacetamide or in the presence of asuitable Pd catalyst and phosphine ligand in a suitable solvent such asdioxane.

It will be appreciated that a compound of formula (I) may be transformedinto another compound of formula (I) using conditions well known in theart.

Compounds of formula (IIIa), (IIIb), (IIIc) and (IIId) are eithercommercially available or well known in the art.

It will be appreciated that a compound of formula (II) may betransformed into another compound of formula (II) by techniques such asoxidation, alkylation, reductive amination etc., either listed above orotherwise known in the literature.

A compound of formula (II) where R⁶ is hydrogen and R⁴ and R⁵ form RingA, may be prepared by the reaction of a compound of formula (IV),wherein PG is a suitable protecting group such as trifluoroacetamide,with a compound of formula (V), wherein A is a 2 to 6 membered,optionally substituted, alkylene chain in which 1 carbon may beoptionally replaced with O, N or S, and wherein L¹ is a leaving group(such as halo, tosyl, mesyl etc.), and removal of the protecting groupin the presence of a suitable base such as sodium hydride or potassiumtert-butoxide in a suitable solvent such as tetrahydrofuran orN,N-dimethylformamide, or by using aqueous sodium hydroxide solution anda suitable solvent such as DCM or toluene with a suitable phase transferagent such as tetrabutylammonium bromide.

A compound of formula (II) R⁶ is hydrogen and R⁴ and R⁵ are both methyl,may be prepared by the reaction of a compound of formula (IV), whereinPG is a suitable protecting group such as trifluoroacetamide, with acompound of formula (Va), wherein L¹ is a leaving group (such as halo,tosyl, mesyl etc.), and removal of the protecting group in the presenceof a suitable base such as sodium hydride or potassium tert-butoxide ina suitable solvent such as tetrahydrofuran or N,N-dimethylformamide.

A compound of formula (IV) where PG is a suitable protecting group suchas trifluoroacetamide, may be prepared by the reaction of a compound offormula (VI) with the iminoiodane (VII) which can be prepared in situfrom iodobenzene diacetate and trifluoroacetamide in a suitable solventsuch as DCM in the prescence of a suitable base such as magnesium oxideand a catalyst such as rhodium acetate.

A compound of formula (I), where R⁴, R⁵ and R⁶ are hydrogen, may beprepared by reaction of a compound of formula (IV), wherein L² is aleaving group (such as halo or —SMe, etc.), with a compound of formula(IIIa), (IIIb) or (IIIc), wherein X is a suitable group (such as boronicacid or ester) in the presence of a suitable Pd catalyst and phosphineligand in a suitable solvent such as a mixture of N,N-dimethylformamide,dimethoxyethane, water and ethanol, under suitable conditions such asheating in a microwave reactor and removal of the trifluoroacetamideprotecting group. Alternatively, a compound of formula (I), where R⁴, R⁵and R⁶ are hydrogen, may be prepared by reaction of a compound offormula (IV), wherein L² is a leaving group (such as halo or —SMe,etc.), with a compound of formula (IIId), with a suitable base such asNaH, Na₂CO₃, Cs₂CO₃ or K₂CO₃ in a suitable solvent such asN,N-dimethylformamide or N,N-dimethylacetamide or in the presence of asuitable Pd catalyst and phosphine ligand in a suitable solvent such asdioxane and removal of the trifluoroacetamide.

A compound of formula (VI), may be prepared by the reaction of acompound of formula (VIII) using conditions well known in the art.

A compound of formula (VIII), may be prepared by the reaction of acompound of formula (IX), wherein L⁴ is a leaving group (such as halo,tosyl, mesyl etc), with a compound of formula (X) optionally in thepresence of a suitable base such as triethylamine and a solvent such asN,N-dimethylformamide.

A compound of formula (IX), may be prepared by the reaction of acompound of formula (XI) using conditions well known in the art.

A compound of formula (XI), may be prepared by the reaction of acompound of formula (XII) using conditions well known in the art.

A compound of formula (XII), where R¹ is a N-linked heterocycle such asmorpholine, may be prepared by the reaction of a compound of formula(XIII) with a cyclic amine such as morpholine optionally in the presenceof a suitable base such as triethylamine in a suitable solvent such asDCM. A compound of formula (XII), where R¹ is a C-linked heterocyclesuch as dihydropyran, may be prepared by the reaction of a compound offormula (XIII) with a suitable organometallic reagent (such as theboronic acid R¹B(OH)₂ or the boronic ester R¹B(OR)₂ etc.) in thepresence of a suitable metal catalyst (such as palladium or copper) in asuitable solvent such as 1,4-dioxane.

Compounds of formula (XIII), cyclic amines, boronic acids {R¹B(OH)₂} andboronic esters {R¹B(OR)₂} are either commercially available or wellknown in the art.

It will be appreciated that where Ring A, is a heterocyclic ringcontaining a nitrogen atom that the nitrogen atom may be suitablyprotected (for example a t-butoxycarbamate or benzyl group) and that theprotecting group may be removed and if necessary a further reactionperformed on the nitrogen (for example an alkylation, reductiveamination or amidation) at any stage in the synthesis.

It will be appreciated that certain of the various ring substituents inthe compounds of the present invention may be introduced by standardaromatic substitution reactions or generated by conventional functionalgroup modifications either prior to or immediately following theprocesses mentioned above, and as such are included in the processaspect of the invention. For example compounds of formula (I) may beconverted into further compounds of formula (I) by standard aromaticsubstitution reactions or by conventional functional groupmodifications. Such reactions and modifications include, for example,introduction of a substituent by means of an aromatic substitutionreaction, reduction of substituents, alkylation of substituents andoxidation of substituents. The reagents and reaction conditions for suchprocedures are well known in the chemical art. Particular examples ofaromatic substitution reactions include the introduction of a nitrogroup using concentrated nitric acid, the introduction of an acyl groupusing, for example, an acyl halide and Lewis acid (such as aluminiumtrichloride) under Friedel Crafts conditions; the introduction of analkyl group using an alkyl halide and Lewis acid (such as aluminiumtrichloride) under Friedel Crafts conditions; and the introduction of ahalogen group. Particular examples of modifications include thereduction of a nitro group to an amino group by for example, catalytichydrogenation with a nickel catalyst or treatment with iron in thepresence of hydrochloric acid with heating; oxidation of alkylthio toalkylsulfinyl or alkylsulfonyl.

It will also be appreciated that in some of the reactions mentionedherein it may be necessary/desirable to protect any sensitive groups inthe compounds. The instances where protection is necessary or desirableand suitable methods for protection are known to those skilled in theart. Conventional protecting groups may be used in accordance withstandard practice (for illustration see T. W. Green, Protective Groupsin Organic Synthesis, John Wiley and Sons, 1991). Thus, if reactantsinclude groups such as amino, carboxy or hydroxy it may be desirable toprotect the group in some of the reactions mentioned herein.

A suitable protecting group for an amino or alkylamino group is, forexample, an acyl group, for example an alkanoyl group such as acetyl, analkoxycarbonyl group, for example a methoxycarbonyl, ethoxycarbonyl ortert-butoxycarbonyl group, an arylmethoxycarbonyl group, for examplebenzyloxycarbonyl, or an aroyl group, for example benzoyl. Thedeprotection conditions for the above protecting groups necessarily varywith the choice of protecting group. Thus, for example, an acyl groupsuch as an alkanoyl or alkoxycarbonyl group or an aroyl group may beremoved for example, by hydrolysis with a suitable base such as analkali metal hydroxide, for example lithium or sodium hydroxide.Alternatively an acyl group such as a tert-butoxycarbonyl group may beremoved, for example, by treatment with a suitable acid as hydrochloric,sulfuric or phosphoric acid or trifluoroacetic acid and anarylmethoxycarbonyl group such as a benzyloxycarbonyl group may beremoved, for example, by hydrogenation over a catalyst such aspalladium-on-carbon, or by treatment with a Lewis acid for example borontris(trifluoroacetate). A suitable alternative protecting group for aprimary amino group is, for example, a phthaloyl group which may beremoved by treatment with an alkylamine, for exampledimethylaminopropylamine, or with hydrazine.

A suitable protecting group for a hydroxy group is, for example, an acylgroup, for example an alkanoyl group such as acetyl, an aroyl group, forexample benzoyl, or an arylmethyl group, for example benzyl. Thedeprotection conditions for the above protecting groups will necessarilyvary with the choice of protecting group. Thus, for example, an acylgroup such as an alkanoyl or an aroyl group may be removed, for example,by hydrolysis with a suitable base such as an alkali metal hydroxide,for example lithium or sodium hydroxide. Alternatively an arylmethylgroup such as a benzyl group may be removed, for example, byhydrogenation over a catalyst such as palladium-on-carbon.

A suitable protecting group for a carboxy group is, for example, anesterifying group, for example a methyl or an ethyl group which may beremoved, for example, by hydrolysis with a base such as sodiumhydroxide, or for example a tert-butyl group which may be removed, forexample, by treatment with an acid, for example an organic acid such astrifluoroacetic acid, or for example a benzyl group which may beremoved, for example, by hydrogenation over a catalyst such aspalladium-on-carbon.

The protecting groups may be removed at any convenient stage in thesynthesis using conventional techniques well known in the chemical art.

Many of the intermediates defined herein are novel and these areprovided as a further feature of the invention.

Biological Assays

The following assays can be used to measure the effects of the compoundsof the present invention as ATR kinase inhibitors.

(a) Enzyme Assay—ATR

ATR for use in the in vitro enzyme assay was obtained from HeLa nuclearextract (CIL Biotech, Mons, Belgium) by immunoprecipitation with rabbitpolyclonal antiserum raised to amino acids 400-480 of ATR (Tibbetts R Set al, 1999, Genes Dev. 13:152-157) contained in the following buffer(25 mM HEPES (pH7.4), 2 mM MgCl₂, 250 mM NaCl, 0.5 mM EDTA, 0.1 mMNa₃VO₄, 10% v/v glycerol, and 0.01% v/v Tween 20). ATR-antibodycomplexes were isolated from nuclear extract by incubating with proteinA-Sepharose beads (Sigma, #P3476) for 1 hour and then throughcentrifugation to recover the beads. In the well of a 96-well plate, 10μL ATR-containing Sepharose beads were incubated with 1 μg of substrateglutathione S-transferase-p53N66 (NH₂-terminal 66 amino acids of p53fused to glutathione S-transferase was expressed in E. coli) in ATRassay buffer (50 mM HEPES (pH 7.4), 150 mM NaCl, 6 mM MgCl₂, 4 mM MnCl₂,0.1 mM Na₃VO₄, 0.1 mM DTT, and 10% (v/v) glycerol) at 37° C. in thepresence or absence of inhibitor. After 10 minutes with gentle shaking,ATP was added to a final concentration of 3 μM and the reactioncontinued at 37° C. for an additional 1 hour. The reaction was stoppedby addition of 100 μL PBS and the reaction was transferred to a whiteopaque glutathione coated 96-well plate (NUNC #436033) and incubatedovernight at 4° C. This plate was then washed with PBS/0.05% (v/v) Tween20, blotted dry, and analyzed by a standard ELISA (Enzyme-LinkedImmunoSorbent Assay) technique with a phospho-serine 15 p53 (16G78)antibody (Cell Signaling Technology, #9286). The detection ofphosphorylated glutathione S-transferase-p53N66 substrate was performedin combination with a goat anti-mouse horseradish peroxidase-conjugatedsecondary antibody (Pierce, #31430). Enhanced chemiluminescence solution(NEN, Boston, Mass.) was used to produce a signal and chemiluminescentdetection was carried out via a TopCount (Packard, Meriden, Conn.) platereader.

The resulting calculated % enzyme activity (Activity Base, IDBS) wasthen used to determine the IC₅₀ values for the compounds (IC₅₀ taken asthe concentration at which 50% of the enzyme activity is inhibited).

(b) Cellular Assays—ATR

ATM and ATR have distinct and overlapping responses to DNA damage. Theymust participate together and responses must be co-ordinated. Bothpathways may be activated by ionising radiation, however only ATR isactivated by UV. Since UV treatment is not practical for use in a highthroughput cell assay, the UV mimetic 4NQ0 (Sigma) was chosen toactivate the ATR DNA damage response pathway.

Chk1, a downstream protein kinase of ATR, plays a key role in DNA damagecheckpoint control. Activation of Chk1 involves phosphorylation ofSer317 and Ser345 (regarded as the preferential target forphosphorylation/activation by ATR). This assay measures a decrease inphosphorylation of Chk1 (Ser 345) in HT29 colon adenocarcinoma cellsfollowing treatment with compound and the UV mimetic 4NQ0. Compoundsdose ranges were created by diluting in 100% DMSO and then further intoassay media (EMEM, 10% FCS, 1% glutamine) using a Labcyte Echo Acousticdispensing instrument. Cells were plated in 384 well Costar plates at9×10⁴ cells per ml in 40 μL EMEM, 10% FCS, 1% glutamine and grown for 24hrs. Following addition of compound the cells were incubated for 60minutes. A final concentration of 3 μM 4NQ0 (prepared in 100% DMSO) wasthen added using the Labcyte Echo and the cells incubated for a further60mins. The cells are then fixed by adding 40 μL 3.7% v/v formaldehydesolution for 20 minutes. After removal of fix, cells were washed withPBS and permeabilised in 40 μL of PBS containing 0.1% Triton™ X-100.Cells are then washed and 15 μl primary antibody solution (pChk1 Ser345)added and the plates incubated at 4° C. overnight. The primary antibodyis then washed off, and 20 μl secondary antibody solution (goatanti—rabbit Alexa Fluor 488, Invitrogen) and 104 Hoechst 33258(Invitrogen) is added for 90mins at room temperature. The plates arewashed and left in 40 μl PBS. Plates were then read on an ArrayS can Vtiinstrument to determine staining intensities, and dose responses wereobtained and used to determine the IC₅₀ values for the compounds.

(c) Cellular—SRB Assay

The potentiation factor (PF₅₀) for compounds is a measure of the foldincrease in effect of a chemotherapeutic agent, when used in combinationwith an ATR inhibitor. Specifically, this is calculated as a ratio ofthe IC₅₀ of control cell growth in the presence of a chemotherapeuticagent, typically carboplatin, divided by the IC₅₀ of cell growth in thepresence of this agent and the ATR inhibitor of interest. For thispurpose, HT29 cells were seeded at the appropriate density to ensureexponential growth throughout the time of the assay (typically 1000-1500cells) in each well of a 96-well plate, in a volume of 80 μl andincubated overnight at 37° C. Subsequently, cells were dosed with eitherDMSO vehicle, or treated with test compounds at fixed concentrations(typically 1, 0.3 & 0.1 μM). Following a one hour incubation at 37° C.,the cells were further treated with a 10 point dose response of thechemotherapeutic agent, based on it's known sensitivity (typically30-0.001 ug/ml for carboplatin). Cells were left to grow for 5 days at37° C., after which time cell growth was assessed using thesulforhodamine B (SRB) assay (Skehan, P et al, 1990 New colorimetriccytotoxic assay for anticancer-drug screening. J. Natl. Cancer Inst. 82,1107-1112.). Specifically, the media was removed and cells fixed with100 μl of ice cold 10% (w/v) trichloroacetic acid. The plates were thenincubated at 4° C. for 20 minutes prior to washing 4 times with water.Each well was then stained with 100 μL of 0.4% (w/v) SRB in 1% aceticacid for 20 minutes before a further 4 washes with 1% acetic acid.Plates were then dried for 2 hours at room temperature and the dye wassolubilized by the addition of 100 μL Tris Base pH 8.5 into each well.Plates were shaken before measuring optical density at 564 nm (OD₅₆₄).In order to calculate the PF50, the OD₅₆₄ values obtained for thedose-response curve of chemotherapeutic agent were expressed as apercentage of the value obtained from cells treated with vehicle alone.Similarly, to act as a control for inclusion of the ATR inhibitor,values from the chemotherapeutic agent tested in combination with afixed ATR inhibitor concentration were expressed as a percentage of thevalue obtained from cells treated with the corresponding concentrationof ATR inhibitor alone. From these internally-controlled curves, IC₅₀values were calculated and the PF50 was determined as the ratio of thesevalues, as described above. Compounds are compared using the PF50 valueat concentrations of ATR inhibitor that show minimal growth inhibitionon their own. IC50 values were calculated with XLfit (IDBS, Surrey UK)using the dose response, 4 parameter logistic model #203. Top (max) andbottom (min) curve fitting was free and not locked to 100% to 0%respectively.

The following assays can be used to measure the effects of the compoundsof the present invention as mTOR kinase inhibitors.

Enzyme—mTOR Kinase Assay (Echo)

The assay used AlphaScreen technology (Gray et al., AnalyticalBiochemistry, 2003, 313: 234-245) to determine the ability of testcompounds to inhibit phosphorylation by recombinant mTOR.

A C-terminal truncation of mTOR encompassing amino acid residues 1362 to2549 of mTOR (EMBL Accession No. L34075) was stably expressed as aFLAG-tagged fusion in HEK293 cells as described by Vilella-Bach et al.,Journal of Biochemistry, 1999, 274, 4266-4272. The HEK293 FLAG-taggedmTOR (1362-2549) stable cell line was routinely maintained at 37° C.with 5% CO₂ up to a confluency of 70-90% in Dulbecco's modified Eagle'sgrowth medium (DMEM; Invitrogen Limited, Paisley, UK Catalogue No.41966-029) containing 10% heat-inactivated foetal calf serum (FCS;Sigma, Poole, Dorset, UK, Catalogue No. F0392), 1% L-glutamine (Gibco,Catalogue No. 25030-024) and 2 mg/ml Geneticin (G418 sulfate; InvitrogenLimited, UK Catalogue No. 10131-027). Following expression in themammalian HEK293 cell line, expressed protein was purified using theFLAG epitope tag using standard purification techniques.

Test compounds were prepared as 10 mM stock solutions in DMSO anddiluted into DMSO as required to give a range of final assayconcentrations. Aliquots (120 nl) of each compound dilution wereacoustically dispensed using a Labcyte Echo 550 into a well of a Greiner384-well low volume (LV) white polystyrene plate (Greiner Bio-one). A12.12 μl mixture of recombinant purified mTOR enzyme, 2 M biotinylatedpeptide substrate(Biotin-Ahx-Lys-Lys-Ala-Asn-Gln-Val-Phe-Leu-Gly-Phe-Thr-Tyr-Val-Ala-Pro-Ser-Val-Leu-Glu-Ser-Val-Lys-Glu-NH₂;Bachem UK Ltd), ATP (20 M) and a buffer solution [comprising Tris-HClpH7.4 buffer (50 mM), EGTA (0.1 mM), bovine serum albumin (0.5 mg/mL),DTT (1.25 mM) and manganese chloride (10 mM)] was incubated at roomtemperature for 120 minutes.

Control wells that produced a maximum signal corresponding to maximumenzyme activity were created by using 100% DMSO instead of testcompound. Control wells that produced a minimum signal corresponding tofully inhibited enzyme were created by adding LY294002 (100 uM)compound. These assay solutions were incubated for 2 hours at roomtemperature.

Each reaction was stopped by the addition of 5 μl of a mixture of EDTA(150 mM), bovine serum albumin (BSA; 0.5 mg/mL) and Tris-HCl pH7.4buffer (50 mM) containing p70 S6 Kinase (T389) 1A5 Monoclonal Antibody(Cell Signalling Technology, Catalogue No. 9206B) and AlphaScreenStreptavidin donor and Protein A acceptor beads (200 ng; Perkin Elmer,Catalogue No. 6760617 respectively) were added and the assay plates wereleft overnight at room temperature in the dark. The resultant signalsarising from laser light excitation at 680 nm were read using a PackardEnvision instrument.

Phosphorylated biotinylated peptide is formed in situ as a result ofmTOR mediated phosphorylation. The phosphorylated biotinylated peptidethat is associated with AlphaScreen Streptavidin donor beads forms acomplex with the p70 S6 Kinase (T389) 1A5 Monoclonal Antibody that isassociated with Alphascreen Protein A acceptor beads. Upon laser lightexcitation at 680 nm, the donor bead: acceptor bead complex produces asignal that can be measured. Accordingly, the presence of mTOR kinaseactivity results in an assay signal. In the presence of an mTOR kinaseinhibitor, signal strength is reduced.

mTOR enzyme inhibition for a given test compound was expressed as anIC₅₀ value.

Cellular—Phospho-Ser473 Akt Assay

This assay determines the ability of test compounds to inhibitphosphorylation of Serine 473 in Akt as assessed using Acumen Explorertechnology (Acumen Bioscience Limited), a plate reader that can be usedto rapidly quantitate features of images generated by laser-scanning.

A MDA-MB-468 human breast adenocarcinoma cell line (LGC Promochem,Teddington, Middlesex, UK, Catalogue No. HTB-132) was routinelymaintained at 37° C. with 5% CO₂ up to a confluency of 70-90% in DMEMcontaining 10% heat-inactivated FCS and 1% L-glutamine.

For the assay, the cells were detached from the culture flask using‘Accutase’ (Innovative Cell Technologies Inc., San Diego, Calif., USA;Catalogue No. AT 104) using standard tissue culture methods andresuspended in media to give 3.75×10⁴ cells per ml. Aliquots (40 μl) ofcells were seeded into each well of a black 384 well plate (Greiner,Catalogue No 781091) to give a density of ˜15000 cells per well. Thecells were incubated overnight at 37° C. with 5% CO₂ to allow them toadhere.

On day 2, the cells were treated with test compounds and incubated for 2hours at 37° C. with 5% CO₂. Test compounds were prepared as 10 mM stocksolutions in DMSO. Compound dosing is performed using acousticdispensing system (Labcyte Echo® Liquid Handling Systems (Labcyte Inc.1190 Borregas Avenue, Sunnyvale, Calif. 94089 USA). As a minimumresponse control, each plate contained wells having a finalconcentration of 100 μM LY294002 (Calbiochem, Beeston, UK, Catalogue No.440202). As a maximum response control, wells contained 1% DMSO insteadof test compound. Following incubation, the contents of the plates werefixed by treatment with a 1.6% aqueous formaldehyde solution (Sigma,Poole, Dorset, UK, Catalogue No. F1635) at room temperature for 1 hour.

All subsequent aspiration and wash steps were carried out using a Tecanplate washer (aspiration speed 10 mm/sec). The fixing solution wasremoved and the contents of the plates were washed withphosphate-buffered saline (PBS; 80 μl; Gibco, Catalogue No. 10010015).The contents of the plates were treated for 10 minutes at roomtemperature with an aliquot (20 μl) of a cell permeabilisation bufferconsisting of a mixture of PBS and 0.5% Tween-20. The ‘permeabilisation’buffer was removed and non-specific binding sites were blocked bytreatment for 1 hour at room temperature of an aliquot (20 μl) of ablocking buffer consisting of 5% dried skimmed milk [‘Marvel’(registered trade mark); Premier Beverages, Stafford, GB] in a mixtureof PBS and 0.05% Tween-20. The ‘blocking’ buffer was removed and thecells were incubated for 1 hour at room temperature with rabbit antiphospho-Akt (Ser473) antibody solution (20 μl per well; Cell Signalling,Hitchin, Herts, U.K., Catalogue No 9277) that had been diluted 1:500 in‘blocking’ buffer. Cells were washed three times in a mixture of PBS and0.05% Tween-20. Subsequently, cells were incubated for 1 hour at roomtemperature with Alexafluor488 labelled goat anti-rabbit IgG (201 perwell; Molecular Probes, Invitrogen Limited, Paisley, UK, Catalogue No.A11008) that had been diluted 1:500 in ‘blocking’ buffer. Cells werewashed 3 times with a mixture of PBS and 0.05% Tween-20. An aliquot ofPBS (50 μl) was added to each well and the plates were sealed with blackplate sealers and the fluorescence signal was detected and analysed.

Fluorescence dose response data obtained with each compound wereanalysed and the degree of inhibition of Serine 473 in Akt was expressedas an IC₅₀ value.

Compounds that show reduced activity against mTOR may ameliorate offtarget effects.

Although the pharmacological properties of the compounds of formula (I)vary with structural change as expected, in general, it is believed thatactivity possessed by compounds of formula (I) may be demonstrated atthe following concentrations or doses in one or more of the above tests(a) to (d):—

-   -   Test (a):—IC₅₀ versus ATR kinase at less than 10 μM, in        particular 0.001-1 μM for many compounds.

The following examples were tested in enzyme assay Test (a):

ATR number of ATR average individual Example IC50 uM tests 1.01 0.034033 2.02 0.003747 3 2.03 0.005607 4

The following examples were tested in cell assay Test (b):

ATR number of ATR average individual Example IC50 uM tests 1.01 0.581 42.01 0.2355 14 2.02 0.05834 36 2.03 0.007053 16 2.04 0.02182 9 2.050.07577 4 2.06 0.01292 2 2.07 0.002578 2 2.08 0.002757 2 2.09 0.1593 22.10 0.109 2 2.11 0.01376 2 3.01 0.01279 4 3.02 0.008428 3 4.01 0.053614 4.02 0.03977 3 4.03 0.05112 2 5.01 0.06255 3 5.02 0.07085 3 5.030.03313 3 5.04 0.01618 3 5.05 0.01828 3 5.06 0.0444 3 5.07 0.02899 25.08 0.01007 2 5.09 0.01796 2 5.10 0.04703 2

The following examples were tested in the Cellular SRB assay Test (c)

Number of individual IC50 Cell Treatment tests ug/ml S.D. PF50 HT29Carboplatin 2 11.798 1.220 HT29 Carboplatin + 2 0.63 0.064 18.721 0.3 uMExample 2.03 HT29 Carboplatin + 2 2.009 0.274 5.887 0.1 uM Example 2.03HT29 Carboplatin + 2 5.740 0.075 2.057 0.03 uM Example 2.03 HT29Carboplatin 2 12.519 1.224 HT29 Carboplatin + 2 2.991 0.507 4.211 0.3 uMExample 2.02 HT29 Carboplatin + 2 6.372 0.073 1.966 0.1 uM Example 2.02HT29 Carboplatin + 2 9.395 0.680 1.331 0.03 uM Example 2.02 Note:averages are arithmetric means.

Note: averages are arithmetric means.

Compounds may be further selected on the basis of further biological orphysical properties which may be measured by techniques known in the artand which may be used in the assessment or selection of compounds fortherapeutic or prophylactic application.

The compounds of the present invention are advantageous in that theypossess pharmacological activity. In particular, the compounds of thepresent invention modulate ATR kinase. The inhibitory properties ofcompounds of formula (I) may be demonstrated using the test proceduresset out herein and in the experimental section. Accordingly, thecompounds of formula (I) may be used in the treatment (therapeutic orprophylactic) of conditions/diseases in human and non-human animalswhich are mediated by ATR kinase.

The invention also provides a pharmaceutical composition comprising acompound of formula (I), or a pharmaceutically acceptable salt thereof,as defined herein in association with a pharmaceutically acceptablediluent or carrier.

The compositions of the invention may be in a form suitable for oral use(for example as tablets, lozenges, hard or soft capsules, aqueous oroily suspensions, emulsions, dispersible powders or granules, syrups orelixirs), for topical use (for example as creams, ointments, gels, oraqueous or oily solutions or suspensions), for administration byinhalation (for example as a finely divided powder or a liquid aerosol),for administration by insufflation (for example as a finely dividedpowder) or for parenteral administration (for example as a sterileaqueous or oily solution for intravenous, subcutaneous, intraperitonealor intramuscular dosing or as a suppository for rectal dosing).

The compositions of the invention may be obtained by conventionalprocedures using conventional pharmaceutical excipients, well known inthe art. Thus, compositions intended for oral use may contain, forexample, one or more colouring, sweetening, flavouring and/orpreservative agents.

The amount of active ingredient that is combined with one or moreexcipients to produce a single dosage form will necessarily varydepending upon the host treated and the particular route ofadministration. For example, a formulation intended for oraladministration to humans will generally contain, for example, from 1 mgto 1 g of active agent (more suitably from 1 to 250 mg, for example from1 to 100 mg) compounded with an appropriate and convenient amount ofexcipients which may vary from about 5 to about 98 percent by weight ofthe total composition.

The size of the dose for therapeutic or prophylactic purposes of acompound of formula I will naturally vary according to the nature andseverity of the disease state, the age and sex of the animal or patientand the route of administration, according to well known principles ofmedicine.

In using a compound of formula (I) for therapeutic or prophylacticpurposes it will generally be administered so that a daily dose in therange, for example, 1 mg/kg to 100 mg/kg body weight is received, givenif required in divided doses. In general, lower doses will beadministered when a parenteral route is employed. Thus, for example, forintravenous administration, a dose in the range, for example, 1 mg/kg to25 mg/kg body weight will generally be used. Similarly, foradministration by inhalation, a dose in the range, for example, 1 mg/kgto 25 mg/kg body weight will be used. Typically, unit dosage forms willcontain about 10 mg to 0.5 g of a compound of this invention.

As stated herein, it is known that ATR kinase have roles intumourigenesis as well as numerous other diseases. We have found thatthe compounds of formula (I) possess potent anti-tumour activity whichit is believed is obtained by way of inhibition of ATR kinase.

Accordingly, the compounds of the present invention are of value asanti-tumour agents. Particularly, the compounds of the present inventionare of value as anti-proliferative, apoptotic and/or anti-invasiveagents in the containment and/or treatment of solid and/or liquid tumourdisease. Particularly, the compounds of the present invention areexpected to be useful in the prevention or treatment of those tumourswhich are sensitive to inhibition of ATR. Further, the compounds of thepresent invention are expected to be useful in the prevention ortreatment of those tumours which are mediated alone or in part by ATR.The compounds may thus be used to produce an ATR enzyme inhibitoryeffect in a warm-blooded animal in need of such treatment.

As stated herein, inhibitors of ATR kinase should be of therapeuticvalue for the treatment of proliferative disease such as cancer and inparticular solid tumours such as carcinoma and sarcomas and theleukaemias and lymphoid malignancies and in particular for treatment of,for example, cancer of the breast, colorectum, lung (including smallcell lung cancer, non-small cell lung cancer and bronchioalveolarcancer) and prostate, and of cancer of the bile duct, bone, bladder,head and neck, kidney, liver, gastrointestinal tissue, oesophagus,ovary, pancreas, skin, testes, thyroid, uterus, cervix and vulva, and ofleukaemias [including chronic lymphocytic leukaemia (CLL), acutelymphoctic leukaemia (ALL) and chronic myelogenous leukaemia (CML)],multiple myeloma and lymphomas.

Anti-cancer effects which are accordingly useful in the treatment ofcancer in a patient include, but are not limited to, anti-tumoureffects, the response rate, the time to disease progression and thesurvival rate. Anti-tumour effects of a method of treatment of thepresent invention include but are not limited to, inhibition of tumourgrowth, tumour growth delay, regression of tumour, shrinkage of tumour,increased time to regrowth of tumour on cessation of treatment, slowingof disease progression. Anti-cancer effects include prophylactictreatment as well as treatment of existing disease.

A ATR kinase inhibitor, or a pharmaceutically acceptable salt thereof,may also be useful for the treatment patients with cancers, including,but not limited to, haematologic malignancies such as leukaemia,multiple myeloma, lymphomas such as Hodgkin's disease, non-Hodgkin'slymphomas (including mantle cell lymphoma), and myelodysplasticsyndromes, and also solid tumours and their metastases such as breastcancer, lung cancer (non-small cell lung cancer (NSCL), small cell lungcancer (SCLC), squamous cell carcinoma), endometrial cancer, tumours ofthe central nervous system such as gliomas, dysembryoplasticneuroepithelial tumour, glioblastoma multiforme, mixed gliomas,medulloblastoma, retinoblastoma, neuroblastoma, germinoma and teratoma,cancers of the gastrointestinal tract such as gastric cancer, oesophagalcancer, hepatocellular (liver) carcinoma, cholangiocarcinomas, colon andrectal carcinomas, cancers of the small intestine, pancreatic cancers,cancers of the skin such as melanomas (in particular metastaticmelanoma), thyroid cancers, cancers of the head and neck and cancers ofthe salivary glands, prostate, testis, ovary, cervix, uterus, vulva,bladder, kidney (including renal cell carcinoma, clear cell and renaloncocytoma), squamous cell carcinomas, sarcomas such as osteosarcoma,chondrosarcoma, leiomyosarcoma, soft tissue sarcoma, Ewing's sarcoma,gastrointestinal stromal tumour (GIST), Kaposi's sarcoma, and paediatriccancers such as rhabdomyosarcomas and neuroblastomas.

The compounds of the present invention and the methods of treatmentcomprising the administering or use of a ATR kinase inhibitor, or apharmaceutically acceptable salt thereof, are expected to beparticularly useful for the treatment of patients with lung cancer,prostate cancer, melanoma, ovarian cancer, breast cancer, endometrialcancer, kidney cancer, gastric cancer, sarcomas, head and neck cancers,tumours of the central nervous system and their metastases, and also forthe treatment of patients with acute myeloid leukaemia.

According to a further aspect of the invention there is provided acompound of formula (I), or a pharmaceutically acceptable salt thereof,as defined herein for use as a medicament in a warm-blooded animal suchas man.

According to a further aspect of the invention, there is provided acompound of formula (I), or a pharmaceutically acceptable salt thereof,as defined herein for use in the production of an anti-proliferativeeffect in a warm-blooded animal such as man.

According to a further aspect of the invention, there is provided acompound of formula (I), or a pharmaceutically acceptable salt thereof,as defined herein for use in the production of an apoptotic effect in awarm-blooded animal such as man.

According to a further feature of the invention there is provided acompound of formula (I), or a pharmaceutically acceptable salt thereof,as defined herein for use in a warm-blooded animal such as man as ananti-invasive agent in the containment and/or treatment of proliferativedisease such as cancer.

According to a further aspect of the invention, there is provided theuse of a compound of formula (I), or a pharmaceutically acceptable saltthereof, as defined herein for the production of an anti-proliferativeeffect in a warm-blooded animal such as man.

According to a further feature of this aspect of the invention there isprovided the use of a compound of formula (I), or a pharmaceuticallyacceptable salt thereof, as defined herein in the manufacture of amedicament for use in the production of an anti-proliferative effect ina warm-blooded animal such as man.

According to a further aspect of the invention, there is provided theuse of a compound of formula (I), or a pharmaceutically acceptable saltthereof, as defined herein for the production of an apoptotic effect ina warm-blooded animal such as man.

According to a further feature of this aspect of the invention there isprovided the use of a compound of formula (I), or a pharmaceuticallyacceptable salt thereof, as defined herein in the manufacture of amedicament for use in the production of an apoptotic effect in awarm-blooded animal such as man.

According to a further feature of the invention there is provided theuse of a compound of formula (I), or a pharmaceutically acceptable saltthereof, as defined herein in the manufacture of a medicament for use ina warm-blooded animal such as man as an anti-invasive agent in thecontainment and/or treatment of proliferative disease such as cancer.

According to a further feature of this aspect of the invention there isprovided a method for producing an anti-proliferative effect in awarm-blooded animal, such as man, in need of such treatment whichcomprises administering to said animal an effective amount of a compoundof formula (I), or a pharmaceutically acceptable salt thereof, asdefined herein.

According to a further feature of this aspect of the invention there isprovided a method for producing an anti-invasive effect by thecontainment and/or treatment of solid tumour disease in a warm-bloodedanimal, such as man, in need of such treatment which comprisesadministering to said animal an effective amount of a compound offormula (I), or a pharmaceutically acceptable salt thereof, as definedherein.

According to a further aspect of the invention there is provided the useof a compound of formula (I), or a pharmaceutically acceptable saltthereof, as defined herein in the manufacture of a medicament for use inthe prevention or treatment of proliferative disease such as cancer in awarm-blooded animal such as man.

According to a further feature of this aspect of the invention there isprovided a method for the prevention or treatment of proliferativedisease such as cancer in a warm-blooded animal, such as man, in need ofsuch treatment which comprises administering to said animal an effectiveamount of a compound of formula (I), or a pharmaceutically acceptablesalt thereof, as defined herein.

According to a further aspect of the invention there is provided acompound of formula (I), or a pharmaceutically acceptable salt thereof,as defined herein for use in the prevention or treatment of thosetumours which are sensitive to inhibition of ATR kinase.

According to a further feature of this aspect of the invention there isprovided the use of a compound of formula (I), or a pharmaceuticallyacceptable salt thereof, as defined herein in the manufacture of amedicament for use in the prevention or treatment of those tumours whichare sensitive to inhibition of ATR kinase.

According to a further feature of this aspect of the invention there isprovided a method for the prevention or treatment of those tumours whichare sensitive to inhibition of ATR kinase which comprises administeringto said animal an effective amount of a compound of formula (I), or apharmaceutically acceptable salt thereof, as defined herein.

According to a further aspect of the invention there is provided acompound of formula (I), or a pharmaceutically acceptable salt thereof,as defined herein for use in providing a ATR kinase inhibitory effect.

According to a further feature of this aspect of the invention there isprovided the use of a compound of formula (I), or a pharmaceuticallyacceptable salt thereof, as defined herein in the manufacture of amedicament for use in providing a ATR kinase inhibitory effect.

According to a further aspect of the invention there is also provided amethod for providing a ATR kinase inhibitory effect which comprisesadministering an effective amount of a compound of formula I, or apharmaceutically acceptable salt thereof, as defined herein.

According to a further feature of the invention there is provided acompound of formula I, or a pharmaceutically acceptable salt thereof, asdefined herein for use in the treatment of cancer, inflammatorydiseases, obstructive airways diseases, immune diseases orcardiovascular diseases.

According to a further feature of the invention there is provided acompound of formula I, or a pharmaceutically acceptable salt thereof, asdefined herein for use in the treatment of solid tumours such ascarcinoma and sarcomas and the leukaemias and lymphoid malignancies.

According to a further feature of the invention there is provided acompound of formula I, or a pharmaceutically acceptable salt thereof, asdefined herein for use in the treatment of cancer of the breast,colorectum, lung (including small cell lung cancer, non-small cell lungcancer and bronchioalveolar cancer) and prostate.

According to a further feature of the invention there is provided acompound of formula (I), or a pharmaceutically acceptable salt thereof,as defined herein for use in the treatment of cancer of the bile duct,bone, bladder, head and neck, kidney, liver, gastrointestinal tissue,oesophagus, ovary, pancreas, skin, testes, thyroid, uterus, cervix andvulva, and of leukaemias (including ALL, CLL and CML), multiple myelomaand lymphomas.

According to a further feature of the invention there is provided acompound of formula (I), or a pharmaceutically acceptable salt thereof,as defined herein for use in the treatment of cancer of the bile duct,bone, bladder, head and neck, kidney, liver, gastrointestinal tissue,oesophagus, ovary, endometrium, pancreas, skin, testes, thyroid, uterus,cervix and vulva, and of leukaemias (including ALL, CLL and CML),multiple myeloma and lymphomas.

According to a further feature of the invention there is provided acompound of formula (I), or a pharmaceutically acceptable salt thereof,as defined herein for use in the treatment of lung cancer, prostatecancer, melanoma, ovarian cancer, breast cancer, endometrial cancer,kidney cancer, gastric cancer, sarcomas, head and neck cancers, tumoursof the central nervous system and their metastases, and also for thetreatment acute myeloid leukaemia.

According to a further feature of the invention there is provided theuse of a compound of formula (I), or a pharmaceutically acceptable saltthereof, as defined herein in the manufacture of a medicament for use inthe treatment of cancer, inflammatory diseases, obstructive airwaysdiseases, immune diseases or cardiovascular diseases.

According to a further feature of the invention there is provided theuse of a compound of formula (I), or a pharmaceutically acceptable saltthereof, as defined herein in the manufacture of a medicament for use inthe treatment of solid tumours such as carcinoma and sarcomas and theleukaemias and lymphoid malignancies.

According to a further feature of the invention there is provided theuse of a compound of formula (I), or a pharmaceutically acceptable saltthereof, as defined herein in the manufacture of a medicament for use inthe treatment of cancer of the breast, colorectum, lung (including smallcell lung cancer, non-small cell lung cancer and bronchioalveolarcancer) and prostate.

According to a further feature of the invention there is provided theuse of a compound of formula (I), or a pharmaceutically acceptable saltthereof, as defined herein in the manufacture of a medicament for use inthe treatment of cancer of the bile duct, bone, bladder, head and neck,kidney, liver, gastrointestinal tissue, oesophagus, ovary, pancreas,skin, testes, thyroid, uterus, cervix and vulva, and of leukaemias(including ALL, CLL and CML), multiple myeloma and lymphomas.

According to a further feature of the invention there is provided theuse of a compound of formula (I), or a pharmaceutically acceptable saltthereof, as defined herein in the manufacture of a medicament for use inthe treatment of lung cancer, prostate cancer, melanoma, ovarian cancer,breast cancer, endometrial cancer, kidney cancer, gastric cancer,sarcomas, head and neck cancers, tumours of the central nervous systemand their metastases, and also for the treatment acute myeloidleukaemia.

According to a further feature of the invention there is provided amethod for treating cancer, inflammatory diseases, obstructive airwaysdiseases, immune diseases or cardiovascular diseases in a warm bloodedanimal such as man that is in need of such treatment which comprisesadministering an effective amount of a compound of formula (I), or apharmaceutically acceptable salt thereof, as defined herein.

According to a further feature of the invention there is provided amethod for treating solid tumours such as carcinoma and sarcomas and theleukaemias and lymphoid malignancies in a warm blooded animal such asman that is in need of such treatment which comprises administering aneffective amount of a compound of formula (I), or a pharmaceuticallyacceptable salt thereof, as defined herein.

According to a further feature of the invention there is provided amethod for treating cancer of the breast, colorectum, lung (includingsmall cell lung cancer, non-small cell lung cancer and bronchioalveolarcancer) and prostate in a warm blooded animal such as man that is inneed of such treatment which comprises administering an effective amountof a compound of formula (I), or a pharmaceutically acceptable saltthereof, as defined herein.

According to a further feature of the invention there is provided amethod for treating cancer of the bile duct, bone, bladder, head andneck, kidney, liver, gastrointestinal tissue, oesophagus, ovary,pancreas, skin, testes, thyroid, uterus, cervix and vulva, and ofleukaemias (including ALL, CLL and CML), multiple myeloma and lymphomasin a warm blooded animal such as man that is in need of such treatmentwhich comprises administering an effective amount of a compound offormula (I), or a pharmaceutically acceptable salt thereof, as definedherein.

According to a further feature of the invention there is provided amethod for treating lung cancer, prostate cancer, melanoma, ovariancancer, breast cancer, endometrial cancer, kidney cancer, gastriccancer, sarcomas, head and neck cancers, tumours of the central nervoussystem and their metastases, and acute myeloid leukaemia in a warmblooded animal such as man that is in need of such treatment whichcomprises administering an effective amount of a compound of formula(I), or a pharmaceutically acceptable salt thereof, as defined herein.

As stated herein, the in vivo effects of a compound of formula (I) maybe exerted in part by one or more metabolites that are formed within thehuman or animal body after administration of a compound of formula (I).

The invention further relates to combination therapies wherein acompound of formula (I), or a pharmaceutically acceptable salt thereof,or a pharmaceutical composition or formulation comprising a compound offormula (I) is administered concurrently or sequentially or as acombined preparation with another treatment of use in the control ofoncology disease.

In particular, the treatment defined herein may be applied as a soletherapy or may involve, in addition to the compounds of the invention,conventional surgery or radiotherapy or chemotherapy. Accordingly, thecompounds of the invention can also be used in combination with existingtherapeutic agents for the treatment of cancer.

Suitable agents to be used in combination include:—

(i) antiproliferative/antineoplastic drugs and combinations thereof, asused in medical oncology such as alkylating agents (for examplecis-platin, carboplatin, cyclophosphamide, nitrogen mustard, melphalan,chlorambucil, busulphan and nitrosoureas); antimetabolites (for exampleantifolates such as fluoropyrimidines like 5-fluorouracil and tegafur,raltitrexed, methotrexate, cytosine arabinoside, hydroxyurea andgemcitabine); antitumour antibiotics (for example anthracyclines likeadriamycin, bleomycin, doxorubicin, daunomycin, epirubicin, idarubicin,mitomycin-C, dactinomycin and mithramycin); antimitotic agents (forexample vinca alkaloids like vincristine, vinblastine, vindesine andvinorelbine and taxoids like paclitaxel and taxotere); and topoisomeraseinhibitors (for example epipodophyllotoxins like etoposide andteniposide, amsacrine, topotecan and camptothecins);(ii) cytostatic agents such as antioestrogens (for example tamoxifen,toremifene, raloxifene, droloxifene and iodoxyfene), oestrogen receptordown regulators (for example fulvestrant), antiandrogens (for examplebicalutamide, flutamide, nilutamide and cyproterone acetate), LHRHantagonists or LHRH agonists (for example goserelin, leuprorelin andbuserelin), progestogens (for example megestrol acetate), aromataseinhibitors (for example as anastrozole, letrozole, vorazole andexemestane) and inhibitors of 5α-reductase such as finasteride;(iii) anti-invasion agents (for example c-Src kinase family inhibitorslike4-(6-chloro-2,3-methylenedioxyanilino)-7-[2-(4-methylpiperazin-1-yl)ethoxy]-5-tetrahydropyran-4-yloxyquinazoline(AZD0530; International Patent Application WO 01/94341) andN-(2-chloro-6-methylphenyl)-2-{6-[4-(2-hydroxyethyl)piperazin-1-yl]-2-methylpyrimidin-4-ylamino}thiazole-5-carboxamide(dasatinib, BMS-354825; J. Med. Chem., 2004, 47, 6658-6661), andmetalloproteinase inhibitors like marimastat and inhibitors of urokinaseplasminogen activator receptor function);(iv) inhibitors of growth factor function: for example such inhibitorsinclude growth factor antibodies and growth factor receptor antibodies(for example the anti-erbB2 antibody trastuzumab [Herceptin™] and theanti-erbB1 antibody cetuximab [C225]); such inhibitors also include, forexample, tyrosine kinase inhibitors, for example inhibitors of theepidermal growth factor family (for example EGFR family tyrosine kinaseinhibitors such asN-(3-chloro-4-fluorophenyl)-7-methoxy-6-(3-morpholinopropoxy)quinazolin-4-amine(gefitinib, ZD1839),N-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)quinazolin-4-amine(erlotinib, OSI-774) and6-acrylamido-N-(3-chloro-4-fluorophenyl)-7-(3-morpholinopropoxy)quinazolin-4-amine(CI 1033) and erbB2 tyrosine kinase inhibitors such as lapatinib),inhibitors of the hepatocyte growth factor family, inhibitors of theplatelet-derived growth factor family such as imatinib, inhibitors ofserine/threonine kinases (for example Ras/Raf signalling inhibitors suchas farnesyl transferase inhibitors, for example sorafenib (BAY 43-9006))and inhibitors of cell signalling through MEK and/or Akt kinases;(v) antiangiogenic agents such as those which inhibit the effects ofvascular endothelial growth factor, [for example the anti-vascularendothelial cell growth factor antibody bevacizumab (Avastin™) and VEGFreceptor tyrosine kinase inhibitors such as4-(4-bromo-2-fluoroanilino)-6-methoxy-7-(1-methylpiperidin-4-ylmethoxy)quinazoline(ZD6474; Example 2 within WO 01/32651),4-(4-fluoro-2-methylindol-5-yloxy)-6-methoxy-7-(3-pyrrolidin-1-ylpropoxy)quinazoline(AZD2171; Example 240 within WO 00/47212), vatalanib (PTK787; WO98/35985) and SU11248 (sunitinib; WO 01/60814), and compounds that workby other mechanisms (for example linomide, inhibitors of integrinα_(v)β₃₃ function and angiostatin)];(vi) vascular damaging agents such as combretastatin A4 and compoundsdisclosed in International Patent Applications WO 99/02166, WO 00/40529,WO 00/41669, WO 01/92224, WO 02/04434 and WO 02/08213;(vii) antisense therapies, for example those which are directed to thetargets listed above, such as ISIS 2503, an anti-ras antisense agent;(viii) gene therapy approaches, including approaches to replace aberrantgenes such as aberrant p53 or aberrant BRCA1 or BRCA2, GDEPT(gene-directed enzyme pro-drug therapy) approaches such as those usingcytosine deaminase, thymidine kinase or a bacterial nitroreductaseenzyme and approaches to increase patient tolerance to chemotherapy orradiotherapy such as multi-drug resistance gene therapy; and(ix) immunotherapeutic approaches, including ex-vivo and in-vivoapproaches to increase the immunogenicity of patient tumour cells, suchas transfection with cytokines such as interleukin 2, interleukin 4 orgranulocyte-macrophage colony stimulating factor, approaches to decreaseT-cell anergy, approaches using transfected immune cells such ascytokine-transfected dendritic cells, approaches usingcytokine-transfected tumour cell lines and approaches usinganti-idiotypic antibodies.

According to a further aspect of the invention there is provided the useof a compound of formula (I), or a pharmaceutically acceptable saltthereof, in the preparation of a medicament for use as an adjunct incancer therapy or for potentiating tumour cells for treatment withionising radiation or chemotherapeutic agents.

According to another aspect of the invention there is provided acompound of formula (I), or a pharmaceutically acceptable salt thereof,in combination with ionising radiation or chemotherapeutic agents foruse in the treatment of cancer.

The invention will now be further explained by reference to thefollowing illustrative examples.

Unless stated otherwise, starting materials were commercially available.All solvents and commercial reagents were of laboratory grade and wereused as received.

GENERAL EXPERIMENTAL

The invention will now be illustrated in the following Examples inwhich, generally:

(i) operations were carried out at room temperature (RT), i.e. in therange 17 to 25° C. and under an atmosphere of an inert gas such as N₂ orAr unless otherwise stated;(ii) in general, the course of reactions was followed by thin layerchromatography (TLC) and/or analytical high performance liquidchromatography (HPLC) which was usually coupled to a mass spectrometer(LCMS). The reaction times that are given are not necessarily theminimum attainable;(iii) when necessary, organic solutions were dried over anhydrous MgSO₄or Na₂SO₄, work-up procedures were carried out using traditional phaseseparating techniques or by using SCX as described in (xiii),evaporations were carried out either by rotary evaporation in vacuo orin a Genevac HT-4/EZ-2 or Biotage V10;(iv) yields, where present, are not necessarily the maximum attainable,and when necessary, reactions were repeated if a larger amount of thereaction product was required;(v) in general, the structures of the end-products of the formula (I)were confirmed by nuclear magnetic resonance (NMR) and/or mass spectraltechniques; electrospray mass spectral data were obtained using a WatersZMD or Waters ZQ LC/mass spectrometer acquiring both positive andnegative ion data, and generally, only ions relating to the parentstructure are reported; proton NMR chemical shift values were measuredon the delta scale using either a Bruker DPX300 spectrometer operatingat a field strength of 300 MHz, a Bruker DRX 400 operating at 400 MHz, aBruker DRX 500 operating at 500 MHz or a Bruker AV700 operating at 700MHz. Unless otherwise stated, NMR spectra were obtained at 400 MHz ind⁶-dimethylsulfoxide. The following abbreviations have been used: s,singlet; d, doublet; t, triplet; q, quartet; m, multiplet; br, broad;qn, quintet;(vi) Unless stated otherwise compounds containing an asymmetric carbonand/or sulphur atom were not resolved;(vii) Intermediates were not necessarily fully purified but theirstructures and purity were assessed by TLC, analytical HPLC, and/or NMRanalysis and/or mass spectrometry;(viii) unless otherwise stated, flash column chromatography (FCC) wasperformed on Merck Kieselgel silica (Art. 9385) or on reversed phasesilica (Fluka silica gel 90 C18) or on Silicycle cartridges (40-63 msilica, 4 to 330 g weight) or on Grace resolv cartridges (4-120 g) or onRediSep Rf 1.5 Flash columns or on RediSep Rf high performance GoldFlash columns (150-415 g weight) or on RediSep Rf Gold C18Reversed-phase columns (20-40 m silica) either manually or automatedusing an Isco Combi Flash Companion system or similar system;(ix) Preparative reverse phase HPLC (RP HPLC) was performed on C18reversed-phase silica, for example on a Waters ‘Xterra’ or ‘XBridge’preparative reversed-phase column (5 μm silica, 19 mm diameter, 100 mmlength) or on a Phenomenex “Gemini” or ‘AXIA’ preparative reversed-phasecolumn (5 μm silica, 110A, 21.1 mm diameter, 100 mm length) usingdecreasingly polar mixtures as eluent, for example [containing 0.1-5%formic acid or 1-5% aqueous ammonium hydroxide (d=0.88)] as solvent Aand acetonitrile as solvent B or MeOH:MeCN 3:1; a typical procedurewould be as follows: a solvent gradient over 9.5 minutes, at 25 mL perminute, from a 85:15 (or alternative ratio as appropriate) mixture ofsolvents A and B respectively to a 5:95 mixture of solvents A and B;(x) the following analytical HPLC methods were used; in general,reverse-phase silica was used with a flow rate of about 1 mL/minute anddetection was by Electrospray Mass Spectrometry and by UV absorbance ata wavelength of 254 nm. Analytical HPLC was performed on C18reverse-phase silica, on a Phenomenex “Gemini” preparativereversed-phase column (5 μm silica, 110 A, 2 mm diameter, 50 mm length)using decreasingly polar mixtures as eluent, for example decreasinglypolar mixtures of water (containing 0.1% formic acid or 0.1% ammonia) assolvent A and acetonitrile as solvent B or MeOH:MeCN 3:1. A typicalanalytical HPLC method would be as follows: a solvent gradient over 4minutes, at approximately 1 mL per minute, from a 95:5 mixture ofsolvents A and B respectively to a 5:95 mixture of solvents A and B;(xi) Where certain compounds were obtained as an acid-addition salt, forexample a mono-hydrochloride salt or a di-hydrochloride salt, thestoichiometry of the salt was based on the number and nature of thebasic groups in the compound, the exact stoichiometry of the salt wasgenerally not determined, for example by means of elemental analysisdata;(xii) Where reactions refer to the use of a microwave, one of thefollowing microwave reactors were used: Biotage Initiator, PersonalChemistry Emrys Optimizer, Personal Chemistry Smithcreator or CEMExplorer;(xiii) Compounds were purified by strong cation exchange (SCX)chromatography using Isolute SPE flash SCX-2 or SCX-3 columns(International Sorbent Technology Limited, Mid Glamorgan, UK);(xiv) the following preparative chiral HPLC methods were used; ingeneral a flow rate of between 10-350 ml/minute and detection was by UVabsorbance at a typical wavelength of 254 nm. A sample concentration ofabout 1-100 mg/ml was used in a suitable solvent mixture such as MeOH,EtOH or iPA optionally mixed with isohexane or heptane with an injectionvolume of between 0.5-100 ml and run time of between 10-150 minutes anda typical oven temperature of 25-35° C.;(xv) the following analytical chiral HPLC methods were used; in generala flow rate of 1 ml/minute and detection was by UV absorbance at atypical wavelength of 254 nm. A sample concentration of about 1 mg/mlwas used in a suitable solvent such as EtOH with an injection volume ofabout 10 μl and run time of between 10-60 minutes and a typical oventemperature of 25-35° C.;(xvi) the following preparative chiral SFC (supercritical fluidchromatography) methods were used; in general a flow rate of about 70ml/minute and detection was by UV absorbance at a typical wavelength of254 nm. A sample concentration of about 100 mg/ml was used in a suitablesolvent such as MeOH with an injection volume of about 0.5 ml and runtime of between 10-150 minutes and a typical oven temperature of 25-35°C.;(xvii) in general Examples were named using ACD Name Ver 10.06 andintermediate compounds were named using “Structure to Name” part ofChemDraw Ultra 11.0.2 by CambridgeSoft;(xviii) In addition to the ones mentioned above, the followingabbreviations have been used:

DMF N,N- DMA N,N-dimethylacetamide dimethylformamide THF tetrahydrofuranDCM Dichloromethane m/z mass spectrometry peak(s) conc. Concentrated NMP1-methylpyrrolidin-2-one TBAF tetra n-butylammonium DIPEAN,N-diisopropylethylamine fluoride MeOH methanol EtOAc ethyl acetateTBAB tetra n-butylammonium DME 1,2-dimethoxyethane bromide MeCNAcetonitrile DBU 1,8-diazabicyclo[5.4.0]undec-7- Et2O diethyl ether eneAc2O acetic anhydride DMAP 4-dimethylaminopyridine h hour(s) EtOHethanol MTBE Methyl tert-butyl ether

Example 1.014-{4-[(3R)-3-Methylmorpholin-4-yl]-6-[((R)—S-methylsulfonimidoyl)methyl]pyrimidin-2-yl}-1H-pyrrolo[2,3-b]pyridine

(R)-3-Methyl-4-(6-((R)—S-methylsulfonimidoylmethyl)-2-(1-tosyl-1H-pyrrolo[2,3-b]pyridin-4-yl)pyrimidin-4-yl)morpholine(98 mg, 0.18 mmol) was dissolved in MeOH (10 ml) and DCM (10 ml) andheated to 50° C. Sodium hydroxide, 2M aqueous solution (0.159 ml, 0.32mmol) was then added and heating continued for 5 hours. The reactionmixture was evaporated and the residue dissolved in DME:water:MeCN 2:1:1(4 ml) and then purified by preparative HPLC using decreasingly polarmixtures of water (containing 1% NH₃) and MeCN as eluents. Fractionscontaining the desired compound were evaporated and the residuetrituated with Et₂O (1 ml) to afford the title compound (34.6 mg, 49%);¹H NMR (400 MHz, CDCl₃) 1.40 (3H, d), 3.17 (3H, s), 3.39 (1H, tt), 3.62(1H, td), 3.77 (1H, dd), 3.85 (1H, d), 4.08 (1H, dd), 4.18 (1H, d),4.37-4.48 (2H, q), 4.51 (1H, s), 6.59 (1H, s), 7.35 (1H, t), 7.46 (1H,d), 8.06 (1H, d), 8.42 (1H, d), 10.16 (1H, s); m/z: (ES+) MH⁺, 387.19.

The(R)-3-methyl-4-(6-((R)—S-methylsulfonimidoylmethyl)-2-(1-tosyl-1H-pyrrolo[2,3-b]pyridin-4-yl)pyrimidin-4-yl)morpholine,used as starting material, can be prepared as follows:

a) (R)-3-methylmorpholine (7.18 g, 71.01 mmol) and triethylamine (12.87ml, 92.31 mmol) were added to methyl2,4-dichloropyrimidine-6-carboxylate (14.70 g, 71.01 mmol) in DCM (100ml). The resulting mixture was stirred at RT for 18 hours. Water (100ml) was added, the layers separated and extracted with DCM (3×75 ml).The combined organics were dried over MgSO₄, concentrated in vacuo andthe residue triturated with Et₂O to yield (R)-methyl2-chloro-6-(3-methylmorpholino)pyrimidine-4-carboxylate (14.77 g, 77%);¹H NMR (400 MHz, CDCl₃) 1.35 (3H, d), 3.34 (1H, td), 3.55 (1H, td), 3.70(1H, dd), 3.81 (1H, d), 3.97 (3H, s), 4.03 (1H, dd), 4.12 (1H, br s),4.37 (1H, br s), 7.15 (1H, s); m/z: (ESI+) MH⁺, 272.43. The liquors wereconcentrated onto silica and purified by chromatography on silicaeluting with a gradient of 20 to 40% EtOAc in isohexane. Fractionscontaining product were combined and evaporated to afford (R)-methyl2-chloro-6-(3-methylmorpholino)pyrimidine-4-carboxylate (1.659 g, 9%);¹H NMR (400 MHz, CDCl₃) 1.35 (3H, d), 3.33 (1H, td), 3.55 (1H, td), 3.69(1H, dd), 3.80 (1H, d), 3.97 (3H, s), 4.03 (1H, dd), 4.12 (1H, br s),4.36 (1H, br s), 7.15 (1H, s); m/z: (ESI+) MH⁺, 272.43.b) Lithium borohydride, 2M in THF (18 ml, 36.00 mmol) was added dropwiseto (R)-methyl 2-chloro-6-(3-methylmorpholino)pyrimidine-4-carboxylate(16.28 g, 59.92 mmol) in THF (200 ml) at 0° C. over a period of 20minutes under nitrogen. The resulting solution was stirred at 0° C. for30 minutes and then allowed to warm to RT and stirred for a further 18hours. Water (200 ml) was added and the THF evaporated. The aqueouslayer was extracted with EtOAc (2×100 ml) and the organic phasescombined, dried over MgSO₄ and then evaporated to afford(R)-(2-chloro-6-(3-methylmorpholino)pyrimidin-4-yl)methanol (14.54 g,100%) which was used in the next step without purification; ¹H NMR (400MHz, CDCl₃) 1.32 (3H, d), 2.65 (1H, br s), 3.25-3.32 (1H, m), 3.51-3.57(1H, m), 3.67-3.70 (1H, m), 3.78 (1H, d), 3.98-4.09 (2H, m), 4.32 (1H,br s), 4.59 (2H, s), 6.44 (1H, s); m/z: (ESI+) MH⁺, 244.40.c) Methanesulfonyl chloride (4.62 ml, 59.67 mmol) was added dropwise to(R)-(2-chloro-6-(3-methylmorpholino)pyrimidin-4-yl)methanol (14.54 g,59.67 mmol) and triethylamine (8.32 ml, 59.67 mmol) in DCM (250 ml) at25° C. over a period of 5 minutes. The resulting solution was stirred at25° C. for 90 minutes. The reaction mixture was quenched with water (100ml) and extracted with DCM (2×100 ml). The organic phases were combined,dried over MgSO₄, filtered and evaporated to afford(R)-(2-chloro-6-(3-methylmorpholino)pyrimidin-4-yl)methylmethanesulfonate (20.14 g, 105%) which was used in the next step withoutfurther purification; ¹H NMR (400 MHz, CDCl₃) 1.33 (3H, d), 3.13 (3H,s), 3.27-3.34 (1H, m), 3.51-3.57 (1H, m), 3.66-3.70 (1H, m), 3.79 (1H,d), 3.99-4.03 (2H, m), 4.34 (1H, br s), 5.09 (2H, d), 6.52 (1H, s); m/z:(ESI+) MH⁺, 322.83.

Alternatively, this step can be carried out as follows:

In a 3 L fixed reaction vessel with a Huber 360 heater/chiller attached,under a nitrogen atmosphere, triethylamine (0.120 L, 858.88 mmol) wasadded in one go to a stirred solution of(R)-(2-chloro-6-(3-methylmorpholino)pyrimidin-4-yl)methanol (161 g,660.68 mmol) in DCM (7.5 vol) (1.2 L) at 20° C. (3° C. exotherm seen).The mixture was cooled to 5° C. and then methanesulfonyl chloride (0.062L, 792.81 mmol) was added dropwise over 15 minutes, not allowing theinternal temperature to exceed 15° C. The reaction mixture was stirredat 15° C. for 2 hours and then held (not stirring) overnight at RT undera nitrogen atmosphere. Water (1.6 L, 10 vol) was added and the aqueouslayer was separated and then extracted with DCM (2×1.6 L, 2×10 vol). Theorganics were combined, washed with 50% brine/water (1.6 L, 10 vol),dried over magnesium sulphate, filtered and then evaporated to afford amixture of approximately two thirds(R)-(2-chloro-6-(3-methylmorpholino)pyrimidin-4-yl)methylmethanesulfonate and one third(R)-4-(2-chloro-6-(chloromethyl)pyrimidin-4-yl)-3-methylmorpholine (216g) which was used in the next step without further purification.

d) Lithium iodide (17.57 g, 131.27 mmol) was added to(R)-(2-chloro-6-(3-methylmorpholino)pyrimidin-4-yl)methylmethanesulfonate (19.2 g, 59.67 mmol) in dioxane (300 ml) and heated to100° C. for 2 hours under nitrogen. The reaction mixture was quenchedwith water (200 ml) and extracted with EtOAc (3×200 ml). The organiclayers were combined and washed with 2M sodium bisulfite solution (400ml), water (400 ml), brine (400 ml) dried over MgSO₄ and thenevaporated. The residue was triturated with Et₂O to afford(R)-4-(2-chloro-6-(iodomethyl)pyrimidin-4-yl)-3-methylmorpholine (13.89g, 66%); ¹H NMR (400 MHz, CDCl₃) 1.32 (3H, d), 3.28 (1H, td), 3.54 (1H,td), 3.69 (1H, dd), 3.78 (1H, d), 3.98-4.02 (2H, m), 4.21 (2H, s), 4.29(1H, br s), 6.41 (1H, s); m/z: (ESI+) MH⁺, 354.31.

The mother liquors were concentrated down and triturated with Et₂O toafford a further crop of(R)-4-(2-chloro-6-(iodomethyl)pyrimidin-4-yl)-3-methylmorpholine (2.46g, 12%); ¹H NMR (400 MHz, CDCl₃) 1.32 (3H, d), 3.28 (1H, td), 3.54 (1H,td), 3.69 (1H, dd), 3.78 (1H, d), 3.98-4.02 (2H, m), 4.21 (2H, s), 4.30(1H, s), 6.41 (1H, s); m/z: (ESI+) MH⁺, 354.31.

Alternatively, this step can be carried out as follows:

(R)-(2-Chloro-6-(3-methylmorpholino)pyrimidin-4-yl)methylmethanesulfonate (80 g, 248.62 mmol) and lithium iodide (83 g, 621.54mmol) were dissolved in dioxane (300 ml) and then heated at 107° C. for1 hour. The reaction mixture was quenched with water (250 ml), extractedwith EtOAc (3×250 ml), the organic layer was dried over MgSO₄, filteredand evaporated.

The residue was dissolved in DCM and Et2O was added, the mixture waspassed through silica (4 inches) and eluted with Et₂O. Fractionscontaining product were evaporated and the residue was then trituratedwith Et₂O to give a solid which was collected by filtration and driedunder vacuum to afford(R)-4-(2-chloro-6-(iodomethyl)pyrimidin-4-yl)-3-methylmorpholine (75 g,86%); m/z: (ESI+) MH⁺, 354.27.

e) (R)-4-(2-Chloro-6-(iodomethyl)pyrimidin-4-yl)-3-methylmorpholine(17.0 g, 48.08 mmol) was dissolved in DMF (150 ml), to this was addedsodium methanethiolate (3.37 g, 48.08 mmol) and the reaction was stirredfor 1 hour at 25° C. The reaction mixture was quenched with water (50ml) and then extracted with Et₂O (3×50 ml). The organic layer was driedover MgSO₄, filtered and then evaporated. The residue was purified byflash chromatography on silica, eluting with a gradient of 50 to 100%EtOAc in iso-hexane. Pure fractions were evaporated to afford(R)-4-(2-chloro-6-(methylthiomethyl)pyrimidin-4-yl)-3-methylmorpholine(12.63 g, 96%); m/z: (ES+) MH⁺, 274.35.

Alternatively,(R)-4-(2-chloro-6-(methylthiomethyl)pyrimidin-4-yl)-3-methylmorpholine,may be prepared as follows:

In a 3 L fixed vessel, sodium thiomethoxide (21% in water) (216 g,646.69 mmol) was added dropwise over 5 minutes to a stirred solution ofa mixture of approximately two thirds(R)-(2-chloro-6-(3-methylmorpholino)pyrimidin-4-yl)methylmethanesulfonate and one third(R)-4-(2-chloro-6-(chloromethyl)pyrimidin-4-yl)-3-methylmorpholine(130.2 g, 431 mmol) and sodium iodide (1.762 ml, 43.11 mmol) in MeCN (1L) at RT (temperature dropped from 20° C. to 18° C. over the additionand then in the next 5 minutes rose to 30° C.). The reaction mixture wasstirred for 16 hours and then diluted with EtOAc (2 L), and washedsequentially with water (750 ml) and saturated brine (1 L). The organiclayer was dried over MgSO₄, filtered and then evaporated to afford(R)-4-(2-chloro-6-(methylthiomethyl)pyrimidin-4-yl)-3-methylmorpholine(108 g, 91%); ¹H NMR (400 MHz, DMSO-d₆) 1.20 (3H, d), 2.07 (3H, s),3.11-3.26 (1H, m), 3.44 (1H, td), 3.53 (2H, s), 3.59 (1H, dd), 3.71 (1H,d), 3.92 (1H, dd), 3.92-4.04 (1H, br s), 4.33 (1H, s), 6.77 (1H, s);m/z: (ES+) MH⁺, 274.36.

f)(R)-4-(2-Chloro-6-(methylthiomethyl)pyrimidin-4-yl)-3-methylmorpholine(12.63 g, 46.13 mmol) was dissolved in DCM (100 ml), to this was addedmCPBA (7.96 g, 46.13 mmol) in one portion and the reaction mixture wasstirred for 10 minutes at 25° C. An additional portion of mCPBA (0.180g) was added. The reaction mixture was quenched with saturated Na₂CO₃solution (50 ml) and extracted with DCM (3×50 ml). The organic layer wasdried over MgSO₄, filtered and then evaporated. The residue wasdissolved in DCM (80 ml) in a 150 ml conical flask which was placed intoa beaker containing Et₂O (200 ml) and the system covered with laboratoryfilm and then left for 3 days. The obtained crystals were filtered,crushed and sonicated with Et₂O. The crystallisation procedure wasrepeated to afford(R)-4-(2-chloro-6-((R)-methylsulfinylmethyl)pyrimidin-4-yl)-3-methylmorpholineas white needles (3.87 g, 29%); ¹H NMR (400 MHz, CDCl₃) 1.33 (3H, d),2.62 (3H, s), 3.30 (1H, td), 3.53 (1H, td), 3.68 (1H, dd), 3.76 (2H,dd), 3.95 (1H, d), 4.00 (1H, dd), 4.02 (1H, s), 4.32 (1H, s), 6.42 (1H,s).

The remaining liquour from the first vapour diffusion was purified byflash chromatography on silica, eluting with a gradient of 0 to 5% MeOHin DCM. Pure fractions were evaporated to afford(R)-4-(2-chloro-6-((S)-methylsulfinylmethyl)pyrimidin-4-yl)-3-methylmorpholineas an orange gum (5.70 g, 43%); ¹H NMR (400 MHz, CDCl₃) 1.33 (3H, d),2.62 (3H, d), 3.29 (1H, td), 3.54 (1H, td), 3.68 (1H, dd), 3.73-3.82(2H, m), 3.94 (1H, dd), 4.00 (2H, dd), 4.33 (1H, s), 6.42 (1H, s).

Alternatively, this step can be carried out as follows:

Sodium meta-periodate (64.7 g, 302.69 mmol) was added in one portion to(R)-4-(2-chloro-6-(methylthiomethyl)pyrimidin-4-yl)-3-methylmorpholine(82.87 g, 302.69 mmol) in water (500 ml), EtOAc (1000 ml) and MeOH (500ml). The resulting solution was stirred at 20° C. for 16 hours. Sodiummetabisulfite (50 g) was added and the mixture stirred for 30 minutes.The reaction mixture was filtered and then partially evaporated toremove the MeOH. The organic layer was separated, dried over MgSO₄,filtered and then evaporated. The aqueous layer was washed with DCM(3×500 ml). The organic layers were combined, dried over MgSO₄, filteredand then evaporated. The residues were combined and dissolved in DCM(400 ml) and purified by flash chromatography on silica, eluting with agradient of 0 to 5% MeOH in DCM. Fractions containing product wereevaporated and the residue was dissolved in DCM (400 ml) and thendivided into four 450 ml bottles. An aluminium foil cap was placed overthe top of each bottle and a few holes made in each cap. The bottleswere placed in pairs in a large dish containing Et₂O (1000 ml), and thencovered and sealed with a second glass dish and left for 11 days. Theresultant white needles were collected by filtration and dried undervacuum. The crystals were dissolved in DCM (200 ml) and placed into a450 ml bottle. An aluminium foil cap was placed over the top of thebottle and a few holes made in the cap. The bottle was placed in a largedish containing Et₂O (1500 ml) and then covered and sealed with a secondglass dish and left for 6 days. The resultant crystals were collected byfiltration and dried under vacuum to afford(R)-4-(2-chloro-6-((R)-methylsulfinylmethyl)pyrimidin-4-yl)-3-methylmorpholine(16.53 g, 19%); ¹H NMR (400 MHz, CDCl₃) 1.33 (3H, d), 2.61 (3H, s), 3.29(1H, td), 3.53 (1H, td), 3.68 (1H, dd), 3.76 (2H, dd), 3.95 (1H, d),3.99 (1H, dd), 4.02 (1H, s), 4.31 (1H, s), 6.41 (1H, s). Chiral HPLC:(HP1100 System 5, 20 μm Chiralpak AD-H (250 mm×4.6 mm) column elutingwith Hexane/EtOH/TEA 50/50/0.1) Rf, 12.192 98.2%.

The filtrate from the first vapour diffusion was concentrated in vacuoto afford an approximate 5:2 mixture of(R)-4-(2-chloro-6-((S)-methylsulfinylmethyl)pyrimidin-4-yl)-3-methylmorpholineand(R)-4-(2-chloro-6-((R)-methylsulfinylmethyl)pyrimidin-4-yl)-3-methylmorpholine(54.7 g, 62%).

Alternatively, this step can be carried out as follows:

Sodium meta-periodate (2.87 g, 13.44 mmol) was added in one portion to(R)-4-(2-chloro-6-(methylthiomethyl)pyrimidin-4-yl)-3-methylmorpholine(3.68 g, 13.44 mmol) in water (10.00 ml), EtOAc (20 ml) and MeOH (10.00ml). The resulting solution was stirred at 20° C. for 16 hours. Thereaction mixture was diluted with DCM (60 ml) and then filtered. The DCMlayer was separated and the aqueous layer washed with DCM (3×40 ml). Theorganics were combined, dried over MgSO₄, filtered and then evaporated.The residue was purified by flash chromatography on silica, eluting witha gradient of 0 to 7% MeOH in DCM. Pure fractions were evaporated toafford(R)-4-(2-chloro-6-(methylsulfinylmethyl)pyrimidin-4-yl)-3-methylmorpholine(2.72 g, 70%); ¹H NMR (400 MHz, DMSO-d₆) 1.22 (3H, d), 2.64 (3H, d),3.14-3.26 (1H, m), 3.45 (1H, td), 3.59 (1H, dd), 3.73 (1H, d), 3.88-3.96(2H, m), 4.00 (1H, d), 4.07 (1H, dt), 4.33 (1H, s), 6.81 (1H, s); m/z:(ESI+) MH⁺, 290.43.

The(3R)-4-(2-chloro-6-(methylsulfinylmethyl)pyrimidin-4-yl)-3-methylmorpholine(2.7 g, 9.32 mmol) was purified by preparative chiral chromatography ona Merck 100 mm 20 μm Chiralpak AD column, eluting isocratically with a50:50:0.1 mixture of iso-Hexane:EtOH:TEA as eluent. The fractionscontaining product were evaporated to afford(R)-4-(2-chloro-6-((S)-methylsulfinylmethyl)pyrimidin-4-yl)-3-methylmorpholine(1.38 g, 51%) as the first eluting compound; ¹H NMR (400 MHz, CDCl₃)1.29 (3H, dd), 2.56 (3H, s), 3.15-3.33 (1H, m), 3.46 (1H, tt), 3.55-3.83(3H, m), 3.85-4.06 (3H, m), 4.31 (1H, s), 6.37 (1H, s). Chiral HPLC:(HP1100 System 6, 20 μm Chiralpak AD (250 mm×4.6 mm) column eluting withiso-Hexane/EtOH/TEA 50/50/0.1) Rf, 7.197 >99%. and(R)-4-(2-chloro-6-((R)-methylsulfinylmethyl)pyrimidin-4-yl)-3-methylmorpholine(1.27 g, 47%) as the second eluting compound; ¹H NMR (400 MHz, CDCl₃)1.28 (3H, d), 2.58 (3H, s), 3.26 (1H, td), 3.48 (1H, td), 3.62 (1H, dt),3.77 (2H, dd), 3.88-4.13 (3H, m), 4.28 (1H, s), 6.37 (1H, s). ChiralHPLC: (HP1100 System 6, 20 μm Chiralpak AD (250 mm×4.6 mm) columneluting with iso-Hexane/EtOH/TEA 50/50/0.1) Rf, 16.897 >99%.

g) Iodobenzene diacetate (18.98 g, 58.94 mmol) was added to(R)-4-(2-chloro-6-((R)-methylsulfinylmethyl)pyrimidin-4-yl)-3-methylmorpholine(17.08 g, 58.94 mmol), 2,2,2-trifluoroacetamide (13.33 g, 117.88 mmol),magnesium oxide (9.50 g, 235.76 mmol) and rhodium(II) acetate dimer(0.651 g, 1.47 mmol) in DCM (589 ml) under air. The resulting suspensionwas stirred at 20° C. for 24 hours. Further 2,2,2-trifluoroacetamide(13.33 g, 117.88 mmol), magnesium oxide (9.50 g, 235.76 mmol),iodobenzene diacetate (18.98 g, 58.94 mmol) and rhodium(II) acetatedimer (0.651 g, 1.47 mmol) were added and the suspension was stirred at20° C. for 3 days. The reaction mixture was filtered and then silica gel(100 g) added to the filtrate and the solvent removed in vacuo. Theresulting powder was purified by flash chromatography on silica, elutingwith a gradient of 20 to 50% EtOAc in isohexane. Pure fractions wereevaporated to affordN—[({2-chloro-6-[(3R)-3-methylmorpholin-4-yl]pyrimidin-4-yl}methyl)(methyl)oxido-λ6-(R)-sulfanylidene]-2,2,2-trifluoroacetamide(19.39 g, 82%); ¹H NMR (400 MHz, DMSO-d₆) 1.22 (3H, d), 3.17-3.27 (1H,m), 3.44 (1H, td), 3.59 (1H, dd), 3.62 (3H, s), 3.74 (1H, d), 3.95 (1H,dd), 4.04 (1H, br s), 4.28 (1H, s), 5.08 (2H, q), 6.96 (1H, s); m/z:(ESI+) MH⁺, 401.12 and 403.13.

h) Dichlorobis(triphenylphosphine)palladium(II) (8.10 mg, 0.01 mmol) wasadded in one portion toN-[({2-chloro-6-[(3R)-3-methylmorpholin-4-yl]pyrimidin-4-yl}methyl)(methyl)oxido-λ6-(R)-sulfanylidene]-2,2,2-trifluoroacetamide(185 mg, 0.46 mmol), 2M aqueous Na₂CO₃ solution (0.277 ml, 0.55 mmol)and4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine(193 mg, 0.48 mmol) in DME:water 4:1 (5 ml) at RT. The reaction mixturewas stirred at 90° C. for 1 hour, filtered and then purified bypreparative HPLC using decreasingly polar mixtures of water (containing1% NH₃) and MeCN as eluents. Fractions containing the desired compoundwere evaporated to afford(R)-3-methyl-4-(6-((R)—S-methylsulfonimidoylmethyl)-2-(1-tosyl-1H-pyrrolo[2,3-b]pyridin-4-yl)pyrimidin-4-yl)morpholine(102 mg, 41%); ¹H NMR (400 MHz, CDCl₃) 1.33 (3H, d), 3.21-3.38 (1H, m),3.42 (3H, d), 3.45-3.57 (1H, m), 3.61-3.70 (1H, m), 3.78 (1H, d), 4.01(1H, dd), 3.90-4.15 (1H, br s), 4.30 (1H, s), 4.64 (1H, dd), 4.84 (1H,dd), 6.49 (1H, d); m/z: (ESI+) MH⁺, 541.35

The4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine,used as starting material, can be prepared as follows:

a) To a 3 L fixed vessel was charged 3-chlorobenzoperoxoic acid (324 g,1444.67 mmol) portionwise to 1H-pyrrolo[2,3-b]pyridine (150 g, 1244.33mmol) in DME (750 ml) and heptane (1500 ml) at 20° C. over a period of 1hour under nitrogen. The resulting slurry was stirred at 20° C. for 18hours. The precipitate was collected by filtration, washed withDME/heptane (½ 5 vol) (750 ml) and dried under vacuum at 40° C. toafford 1H-pyrrolo[2,3-b]pyridine 7-oxide 3-chlorobenzoate (353 g, 97%)as a cream solid, which was used without further purification; ¹H NMR(400 MHz, DMSO-d₆) 6.59 (1H, d), 7.07 (1H, dd), 7.45 (1H, d), 7.55 (1H,t), 7.65 (1H, dd), 7.70 (1H, ddd), 7.87-7.93 (2H, m), 8.13 (1H, d),12.42 (1H, s), 13.32 (1H, s).b) A 2M solution of potassium carbonate (910 ml, 1819.39 mmol) was addeddropwise to a stirred slurry of 1H-pyrrolo[2,3-b]pyridine 7-oxide3-chlorobenzoate (352.6 g, 1212.93 mmol) in water (4.2 vol) (1481 ml) at20° C., over a period of 1 hour adjusting the pH to 10. To the resultingslurry was charged water (2 vol) (705 ml) stirred at 20° C. for 1 hour.The slurry was cooled to 0° C. for 1 hour and the slurry filtered, thesolid was washed with water (3 vol 1050 ml) and dried in a vacuum ovenat 40° C. over P₂O₅ overnight to afford 1H-pyrrolo[2,3-b]pyridine7-oxide (118 g, 73%); ¹H NMR (400 MHz, DMSO-d₆) 6.58 (1H, d), 7.06 (1H,dd), 7.45 (1H, d), 7.64 (1H, d), 8.13 (1H, d), 12.44 (1H, s); m/z: (ES+)(MH+MeCN)⁺, 176.03.c) To a 3 L fixed vessel under an atmosphere of nitrogen was chargedmethanesulfonic anhydride (363 g, 2042.71 mmol) portionwise to1H-pyrrolo[2,3-b]pyridine 7-oxide (137 g, 1021.36 mmol), andtetramethylammonium bromide (236 g, 1532.03 mmol) in DMF (10 vol) (1370ml) cooled to 0° C. over a period of 30 minutes under nitrogen. Theresulting suspension was stirred at 20° C. for 24 hours. The reactionmixture was quenched with water (20 vol, 2740 ml) and the reactionmixture was adjusted to pH 7 with 50% sodium hydroxide (approx 200 ml).Water (40 vol, 5480 ml) was charged and the mixture cooled to 10° C. for30 minutes. The solid was filtered, washed with water (20 vol, 2740 ml)and the solid dissolved into DCM/methanol (4:1, 2000 ml), dried overMgSO₄ and evaporated to provide a light brown solid. The solid was takenup in hot methanol (2000 ml) and water added dropwise until the solutionwent turbid and left overnight. The solid was filtered off anddiscarded, the solution was evaporated and the solid recrystallised fromMeCN (4000 ml). The solid was filtered and washed with MeCN to afford4-bromo-1H-pyrrolo[2,3-b]pyridine (68.4 g, 34%) as a pink solid; ¹H NMR(400 MHz, DMSO-d₆) 6.40-6.45 (1H, m), 7.33 (1H, d), 7.57-7.63 (1H, m),8.09 (1H, t), 12.02 (1H, s); m/z: (ES+) MH⁺, 198.92. The crude motherliquors were purified by Companion RF (reverse phase C18, 415 g column),using decreasingly polar mixtures of water (containing 1% NH₃) and MeCNas eluents (starting at 26% upto 46% MeCN). Fractions containing thedesired compound were evaporated to afford4-bromo-1H-pyrrolo[2,3-b]pyridine (5.4 g, 3%) as a pink solid; ¹H NMR(400 MHz, DMSO-d₆) 6.43 (1H, dd), 7.33 (1H, d), 7.55-7.66 (1H, m), 8.09(1H, d), 12.03 (1H, s); m/z: (ES+) MH⁺, 199.22.d) Sodium hydroxide (31.4 ml, 188.35 mmol) was added to4-bromo-1H-pyrrolo[2,3-b]pyridine (10.03 g, 50.91 mmol), tosyl chloride(19.41 g, 101.81 mmol) and tetrabutylammonium hydrogensulfate (0.519 g,1.53 mmol) in DCM (250 ml) at RT. The resulting mixture was stirred atRT for 1 hour. The reaction was quenched through the addition ofsaturated aqueous NH₄Cl, the organic layer removed and the aqueous layerfurther extracted with DCM (3×25 ml). The combined organics were washedwith brine (100 ml), dried over Na₂SO₄ and then concentrated underreduced pressure. The residue was purified by flash chromatography onsilica, eluting with a gradient of 0 to 20% EtOAc in isohexane. Purefractions were evaporated to afford4-bromo-1-tosyl-1H-pyrrolo[2,3-b]pyridine (14.50 g, 81%); ¹H NMR (400MHz, CDCl₃) 2.38 (3H, s), 6.64 (1H, d), 7.28 (2H, d), 7.36 (1H, d), 7.78(1H, d), 8.06 (2H, d), 8.22 (1H, d); m/z: (ES+) MH⁺, 353.23.e) 1,1′-Bis(diphenylphosphino)ferrocenedichloropalladium(II) (3.37 g,4.13 mmol) was added in one portion to4-bromo-1-tosyl-1H-pyrrolo[2,3-b]pyridine (14.5 g, 41.28 mmol),bis(pinacolato)diboron (20.97 g, 82.57 mmol) and potassium acetate(12.16 g, 123.85 mmol) in anhydrous DMF (300 ml) at RT. The resultingmixture was stirred under nitrogen at 90° C. for 24 hours. After coolingto RT, 1N aqueous NaOH was added until the aqueous layer was taken to pH10. The aqueous layer was washed with DCM (1 L), carefully acidified topH 4 with 1 N aqueous HCl, and then extracted with DCM (3×300 ml). Theorganic layer was concentrated under reduced pressure to afford a darkbrown solid. The solid was triturated with diethyl ether, filtered anddried to afford4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine(7.058 g, 43%); ¹H NMR (400 MHz, CDCl₃) 1.36 (12H, s), 2.35 (3H, s),7.01 (1H, d), 7.22 (2H, d), 7.52 (1H, d), 7.74 (1H, d), 8.03 (2H, m),8.42 (1H, d); m/z: (ES+) MH⁺, 399.40. The mother liquors wereconcentrated in vacuo and the residue triturated in isohexane, filteredand dried to afford a further sample of4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine(3.173 g, 19%); ¹H NMR (400 MHz, CDCl₃) 1.36 (12H, s), 2.35 (3H, s),7.01 (1H, d), 7.23 (2H, d), 7.52 (1H, d), 7.74 (1H, d), 8.03 (2H, d),8.42 (1H, d); m/z: (ES+) MH⁺, 399.40.

Example 2.01 and Example 2.024-{4-[(3R)-3-Methylmorpholin-4-yl]-6-[1-((S)—S-methylsulfonimidoyl)cyclopropyl]pyrimidin-2-yl}-1H-pyrrolo[2,3-b]pyridine,and4-{4-[(3R)-3-Methylmorpholin-4-yl]-6-[1-((R)—S-methylsulfonimidoyl)cyclopropyl]pyrimidin-2-yl}-1H-pyrrolo[2,3-b]pyridine

(3R)-3-Methyl-4-(6-(1-(S-methylsulfonimidoyl)cyclopropyl)-2-(1-tosyl-1H-pyrrolo[2,3-b]pyridin-4-yl)pyrimidin-4-yl)morpholine(1.67 g, 2.95 mmol) was dissolved in DME:water 4:1 (60 ml) and heated to50° C. Sodium hydroxide, 2M aqueous solution (2.58 ml, 5.16 mmol) wasthen added and heating continued for 18 hours. The reaction mixture wasacidified with 2M HCl (˜2 ml) to pH5. The reaction mixture wasevaporated to dryness and the residue dissolved in EtOAc (250 ml), andwashed with water (200 ml). The organic layer was dried over MgSO₄,filtered and evaporated onto silica gel (10 g). The resulting powder waspurified by flash chromatography on silica, eluting with a gradient of 0to 7% MeOH in DCM. Pure fractions were evaporated and the residue waspurified by preparative chiral chromatography on a Merck 50 mm, 20 μmChiralCel OJ column, eluting isocratically with 50% isohexane inEtOH/MeOH (1:1) (modified with TEA) as eluent. The fractions containingthe desired compound were evaporated to dryness to afford the titlecompound:4-{4-[(3R)-3-methylmorpholin-4-yl]-6-[1-((R)—S-methylsulfonimidoyl)cyclopropyl]pyrimidin-2-yl}-1H-pyrrolo[2,3-b]pyridine(0.538 g, 44%) as the first eluting compound; ¹H NMR (400 MHz, DMSO-d⁶)1.29 (3H, d), 1.51 (3H, m), 1.70-1.82 (1H, m), 3.11 (3H, s), 3.28 (1H,m, obscured by water peak), 3.48-3.60 (1H, m), 3.68 (1H, dd), 3.75-3.87(2H, m), 4.02 (1H, dd), 4.19 (1H, d), 4.60 (1H, s), 7.01 (1H, s), 7.23(1H, dd), 7.51-7.67 (1H, m), 7.95 (1H, d), 8.34 (1H, d), 11.76 (1H, s);m/z: (ES+) MH⁺, 413.12. Chiral HPLC: (HP1100 System 4, 5 μm ChiralcelOJ-H (250 mm×4.6 mm) column eluting with iso-Hexane/EtOH/MeOH/TEA50/25/25/0.1) Rf, 9.013 >99%. Crystals were grown and isolated by slowevaporation to dryness in air from EtOAc. These crystals were used toobtain the structure shown in FIG. 1 by X-Ray diffraction (see below).Example 2.02:4-{4-[(3R)-3-methylmorpholin-4-yl]-6-[1-((R)—S-methylsulfonimidoyl)cyclopropyl]pyrimidin-2-yl}-1H-pyrrolo[2,3-b]pyridine(326 mg, 0.79 mmol) was dissolved in DCM (3 ml). Silica gel (0.5 g) wasadded and the mixture concentrated in vacuo. The resulting powder waspurified by flash chromatography on silica, eluting with a gradient of 0to 5% MeOH in DCM. Pure fractions were evaporated to dryness and theresidue was crystallized from EtOAc/n-heptane to afford4-{4-[(3R)-3-methylmorpholin-4-yl]-6-[1-((R)—S-methylsulfonimidoyl)cyclopropyl]pyrimidin-2-yl}-1H-pyrrolo[2,3-b]pyridine(256 mg, 79%) as a white crystalline solid; ¹H NMR (400 MHz, DMSO-d⁶)1.29 (3H, d), 1.39-1.60 (3H, m), 1.71-1.81 (1H, m), 3.10 (3H, d),3.21-3.29 (1H, m), 3.52 (1H, td), 3.67 (1H, dd), 3.80 (2H, t), 4.01 (1H,dd), 4.19 (1H, d), 4.59 (1H, s), 7.01 (1H, s), 7.23 (1H, dd), 7.54-7.62(1H, m), 7.95 (1H, d), 8.34 (1H, d), 11.75 (1H, s). DSC (Mettler-ToledoDSC 820, sample run at a heating rate of 10° C. per minute from 30° C.to 350° C. in a pierced aluminium pan) peak, 224.11° C.

and the title compound:4-{4-[(3R)-3-methylmorpholin-4-yl]-6-[1-((S)—S-methylsulfonimidoyl)cyclopropyl]pyrimidin-2-yl}-1H-pyrrolo[2,3-b]pyridine(0.441 g, 36%) as the second eluting compound; ¹H NMR (400 MHz, DMSO-d⁶)1.28 (3H, d), 1.40-1.58 (3H, m), 1.70-1.80 (1H, m), 3.10 (3H, d),3.23-3.27 (1H, m), 3.51 (1H, dt), 3.66 (1H, dd), 3.80 (2H, d), 4.01 (1H,dd), 4.21 (1H, d), 4.56 (1H, s), 6.99 (1H, s), 7.22 (1H, dd), 7.54-7.61(1H, m), 7.94 (1H, d), 8.33 (1H, d), 11.75 (1H, s); m/z: (ES+) MH⁺,413.12. Chiral HPLC: (HP1100 System 4, 5 μm Chiralcel OJ-H (250 mm×4.6mm) column eluting with iso-Hexane/EtOH/MeOH/TEA 50/25/25/0.1) Rf,15.685>99%. Example 2.01:4-{4-[(3R)-3-methylmorpholin-4-yl]-6-[1-((S)—S-methylsulfonimidoyl)cyclopropyl]pyrimidin-2-yl}-1H-pyrrolo[2,3-b]pyridine(66.5 mg) was purified by crystallisation from EtOH/water to afford4-{4-[(3R)-3-methylmorpholin-4-yl]-6-[1-((S)—S-methylsulfonimidoyl)cyclopropyl]pyrimidin-2-yl}-1H-pyrrolo[2,3-b]pyridine(0.050 g); ¹H NMR (400 MHz, CDCl₃) 1.40 (3H, d), 1.59 (2H, s), 1.81 (2H,s), 2.41 (1H, s), 3.16 (3H, s), 3.39 (1H, td), 3.59-3.67 (1H, m), 3.77(1H, dd), 3.86 (1H, d), 4.07 (1H, dd), 4.17 (1H, d), 4.54 (1H, s), 6.91(1H, s), 7.34 (1H, t), 7.43 (1H, t), 8.05 (1H, d), 8.41 (1H, d), 9.14(1H, s).

X-Ray Diffraction on Crystal from First Eluted Compound (Structure Shownin FIG. 1)

Crystal data C₂₀H₂₄N₆O₂S Mr = 412.52 V = 1026.4 (2) Å³ Triclinic, P1 Z =2 a = 10.1755 (13) Å Mo Kα radiation, λ = 0.71073 Å b = 10.4411 (13) Å μ= 0.19 mm−1 c = 11.2879 (14) Å T = 200K α = 95.528 (2)° 0.20 × 0.10 ×0.05 mm β = 108.796 (2)° γ = 111.292 (2)° Data collection Bruker APEX-IICCD diffractometer 14550 independent reflections Absorption correction:Multi-scan 9935 reflections with I > 2σ(I) Tmin = 0.964, Tmax = 0.991Rint = 0.024 18381 measured reflections Refinement R[F² > 2σ(F²)] =0.056 H-atom parameters constrained wR(F²) = 0.147 Δρmax = 0.31 e Å⁻³ S= 1.02 Δρmin = −0.38 e Å⁻³ 14550 reflections Absolute structure: Flack HD (1983), Flack parameter: 0.03 Acta Cryst. A39, 876-881 (5) 527parameters 3 restraints

The(3R)-3-methyl-4-(6-(1-(S-methylsulfonimidoyl)cyclopropyl)-2-(1-tosyl-1H-pyrrolo[2,3-b]pyridin-4-yl)pyrimidin-4-yl)morpholine,used as starting material, can be prepared as follows:

a) Iodobenzene diacetate (6.54 g, 20.29 mmol) was added to(3R)-4-(2-chloro-6-(methylsulfinylmethyl)pyrimidin-4-yl)-3-methylmorpholine(5.88 g, 20.29 mmol), 2,2,2-trifluoroacetamide (4.59 g, 40.58 mmol),magnesium oxide (3.27 g, 81.16 mmol) and rhodium(II) acetate dimer(0.224 g, 0.51 mmol) in DCM (169 ml) under air. The resulting suspensionwas stirred at RT for 3 days. Further 2,2,2-trifluoroacetamide (1.15 g,10.15 mmol), magnesium oxide (0.818 g, 20.29 mmol), rhodium(II) acetatedimer (0.056 g, 0.13 mmol) and iodobenzene diacetate (1.64 g, 5.07 mmol)were added and the suspension was stirred at RT for a further 24 hours.The reaction mixture was filtered and silica gel (3 g) was added to thefiltrate and then the mixture was evaporated. The resulting powder waspurified by flash chromatography on silica, eluting with a gradient of20 to 50% EtOAc in isohexane. Fractions containing product wereevaporated and the residue was triturated with isohexane/methyltert-butylether to give a solid which was collected by filtration anddried under vacuum to affordN—[({2-chloro-6-[(3R)-3-methylmorpholin-4-yl]pyrimidin-4-yl}methyl)(methyl)oxido-λ6-sulfanylidene]-2,2,2-trifluoroacetamide(6.64 g, 82%); ¹H NMR (400 MHz, CDCl₃) 1.33 (3H, d), 3.28 (1H, dd), 3.43(3H, d), 3.46-3.59 (1H, m), 3.62-3.71 (1H, m), 3.79 (1H, d), 3.90-4.50(2H, br s), 4.21 (1H, s), 4.66 (1H, dd), 4.86 (1H, dd), 6.50 (1H, d);m/z: (ES+) MH⁺, 401.01, 402.93.b) Sodium hydroxide (Sigma-Aldrich 415413, d=1.515 g/ml, 50 ml of a 50%solution, 937.57 mmol) was added toN—[({2-chloro-6-[(3R)-3-methylmorpholin-4-yl]pyrimidin-4-yl}methyl)(methyl)oxido-λ6-sulfanylidene]-2,2,2-trifluoroacetamide(5.2 g, 12.97 mmol), 1,2-dibromoethane (4.47 ml, 51.90 mmol) andtetrabutylammonium hydrogensulfate (0.441 g, 1.30 mmol) in toluene (500ml). The resulting mixture was stirred at RT for 24 hours. Further1,2-dibromoethane (1.00 ml, 11.60 mmol) was added and the mixture wasstirred at RT for a further 2 hours. The reaction mixture was dilutedwith EtOAc (500 ml), and washed sequentially with water (750 ml) andsaturated brine (100 ml). The organic layer was dried over MgSO₄,filtered and evaporated. The residue was dissolved in DCM (100 ml) andthen purified by flash chromatography on silica, eluting with a gradientof 0 to 5% MeOH in DCM.

Pure fractions were evaporated to dryness to afford(3R)-4-(2-chloro-6-(1-(S-methylsulfonimidoyl)cyclopropyl)pyrimidin-4-yl)-3-methylmorpholine(1.383 g, 32%); ¹H NMR (400 MHz, CDCl₃) 1.32 (3H, d), 1.39-1.48 (2H, m),1.69-1.77 (2H, m), 3.12 (3H, s), 3.22-3.36 (1H, m), 3.54 (1H, td), 3.68(1H, dd), 3.78 (1H, d), 3.90-4.10 (1H, br s), 4.00 (1H, dd), 4.33 (1H,br s), 6.79 (1H, d); m/z: (ES+) MH⁺, 331.08, 333.00.

Alternatively, this step can be performed as follows:

Sodium hydroxide (Sigma-Aldrich 415413, d=1.515 g/ml, 217 ml of a 50%solution, 4059.84 mmol) was added toN—[({2-chloro-6-[(3R)-3-methylmorpholin-4-yl]pyrimidin-4-yl}methyl)(methyl)oxido-λ6-sulfanylidene]-2,2,2-trifluoroacetamide(27.12 g, 67.66 mmol), 1,2-dibromoethane (23.32 ml, 270.66 mmol) andtetraoctylammonium bromide (3.70 g, 6.77 mmol) in methyl THF (1000 ml)at 20° C. under nitrogen. The resulting mixture was stirred at 20° C.for 24 hours. Further 1,2-dibromoethane (23.32 ml, 270.66 mmol) wasadded and the mixture was stirred at 20° C. for a further 24 hours. Thereaction mixture was diluted with methyl THF (1000 ml) and the aqueouslayer separated. The organic layer was diluted further with EtOAc (1000ml) and washed with water (1500 ml). The organic layer was dried overMgSO₄, filtered and then evaporated. The residue was purified by flashchromatography on silica, eluting with a gradient of 0 to 5% MeOH inDCM. Pure fractions were evaporated to afford(3R)-4-(2-chloro-6-(1-(S-methylsulfonimidoyl)cyclopropyl)pyrimidin-4-yl)-3-methylmorpholine(14.80 g, 66%); ¹H NMR (400 MHz, DMSO-d⁶) 1.21 (3H, d), 1.39 (3H, m),1.62-1.71 (1H, m), 3.01 (3H, s), 3.43 (1H, tt), 3.58 (1H, dd), 3.72 (1H,d), 3.82 (1H, d), 3.93 (1H, dd), 4.01 (1H, s), 4.38 (1H, s), 6.96 (1H,d); m/z: (ES+) MH⁺, 331.46 and 333.43.

d) Dichlorobis(triphenylphosphine)palladium(II) (0.073 g, 0.10 mmol) wasadded in one portion to(3R)-4-(2-chloro-6-(1-(S-methylsulfonimidoyl)cyclopropyl)pyrimidin-4-yl)-3-methylmorpholine(1.383 g, 4.18 mmol), 2M aqueous sodium carbonate solution (2.508 ml,5.02 mmol) and4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine(1.665 g, 4.18 mmol) in DME:water 4:1 (100 ml) under nitrogen. Thereaction mixture was stirred at 90° C. for 6 hours. The reaction mixturewas concentrated and diluted with EtOAc (400 ml), and washedsequentially with water (300 ml) and saturated brine (75 ml). Theorganic layer was dried over MgSO₄, filtered and evaporated onto silicagel (30 g). The resulting powder was purified by flash chromatography onsilica, eluting with a gradient of 0 to 5% MeOH in DCM. Pure fractionswere evaporated to dryness to afford(3R)-3-methyl-4-(6-(1-(S-methylsulfonimidoyl)cyclopropyl)-2-(1-tosyl-1H-pyrrolo[2,3-b]pyridin-4-yl)pyrimidin-4-yl)morpholine(2.174 g, 92%); ¹H NMR (400 MHz, CDCl₃) 1.37 (3H, d), 1.56 (2H, m), 1.83(2H, q), 2.37 (4H, s), 3.16 (3H, s), 3.36 (1H, td), 3.60 (1H, td), 3.74(1H, dd), 3.85 (1H, d), 4.01-4.19 (2H, m), 4.49 (1H, s), 6.95 (1H, d),7.28 (2H, d, obscured by CDCL3 peak), 7.44 (1H, t), 7.82 (1H, d),8.02-8.11 (3H, m), 8.52 (1H, d); m/z: (ES+) MH⁺, 567.11.

Alternatively, example 2.01 and example 2.02, may be prepared asfollows:

Sodium hydroxide, 2M aqueous solution (9.95 ml, 19.90 mmol) was added to(3R)-3-methyl-4-(6-(1-(S-methylsulfonimidoyl)cyclopropyl)-2-(1-tosyl-1H-pyrrolo[2,3-b]pyridin-4-yl)pyrimidin-4-yl)morpholine(6.44 g, 11.37 mmol) in DME (100 ml)/water (25.00 ml). The resultingsolution was stirred at 50° C. for 18 hours. Further NaOH, 2M aqueoussolution (18 ml, 36.00 mmol) was added and the mixture was stirred at50° C. for a further 3 days. The reaction mixture was acidified with 2MHCl (˜22 ml) to pH5. The reaction mixture was evaporated and the residuewas dissolved in DCM (250 ml) and washed with water (200 ml). Theorganic layer was dried over MgSO₄, filtered and then evaporated toapproximately 50 ml in volume. The solution was purified by flashchromatography on silica, eluting with a gradient of 0 to 7% MeOH inDCM. Pure fractions were evaporated to afford4-{4-[(3R)-3-methylmorpholin-4-yl]-6-[1-(S-methylsulfonimidoyl)cyclopropyl]pyrimidin-2-yl}-1H-pyrrolo[2,3-b]pyridine(2.440 g, 52%); ¹H NMR (400 MHz, DMSO-d⁶) 1.27 (3H, d), 1.42 (1H, dd),1.47-1.58 (2H, m), 1.68-1.80 (1H, m), 3.10 (3H, s), 3.24-3.31 (1H, m),3.51 (1H, t), 3.66 (1H, dd), 3.80 (1H, d), 3.83-3.88 (1H, m), 4.00 (1H,dd), 4.20 (1H, s), 4.57 (1H, s), 6.99 (1H, d), 7.22 (1H, dd), 7.53-7.63(1H, m), 7.94 (1H, d), 8.34 (1H, t), 11.80 (1H, s); m/z: (ES+) MH⁺,413.47.

In a separate experiment, NaOH, 2M aqueous solution (7.60 ml, 15.19mmol) was added to(3R)-3-methyl-4-(6-(1-(S-methylsulfonimidoyl)cyclopropyl)-2-(1-tosyl-1H-pyrrolo[2,3-b]pyridin-4-yl)pyrimidin-4-yl)morpholine(4.92 g, 8.68 mmol) in DME (100 ml)/water (25.00 ml). The resultingsolution was stirred at 50° C. for 18 hours. The reaction mixture wasacidified with 2M HCl (˜5 mL) to pH5. The reaction mixture wasevaporated and the residue was dissolved in DCM (250 ml) and washed withwater (200 ml). The organic layer was dried over MgSO₄, filtered andthen evaporated to approximately 50 ml in volume. The resulting solutionwas purified by flash chromatography on silica, eluting with a gradientof 0 to 7% MeOH in DCM. Pure fractions were evaporated to dryness toafford4-{4-[(3R)-3-methylmorpholin-4-yl]-6-[1-(S-methylsulfonimidoyl)cyclopropyl]pyrimidin-2-yl}-1H-pyrrolo[2,3-b]pyridine(2.160 g, 60%); ¹H NMR (400 MHz, DMSO-d⁶) 1.28 (3H, d), 1.41-1.59 (3H,m), 1.76 (1H, dt), 3.10 (3H, d), 3.31 (1H, d), 3.52 (1H, t), 3.67 (1H,dd), 3.80 (2H, d), 4.01 (1H, dd), 4.21 (1H, d), 4.58 (1H, s), 7.00 (1H,d), 7.22 (1H, dd), 7.54-7.63 (1H, m), 7.95 (1H, d), 8.33 (1H, d), 11.75(1H, s); m/z: (ES+) MH⁺, 413.19.

The two samples of4-{4-[(3R)-3-methylmorpholin-4-yl]-6-[1-(S-methylsulfonimidoyl)cyclopropyl]pyrimidin-2-yl}-1H-pyrrolo[2,3-b]pyridinewere combined (4.56 g, 11.05 mmol) and purified by preparative chiralchromatography on a Merck 100 mm ChiralCel OJ column (1550 g), elutingisocratically with 50% isohexane in EtOH/MeOH (1:1) (modified with TEA)as eluent. The fractions containing the first eluting compound werecombined and evaporated. The residue was dissolved in DCM (50 ml) andconcentrated in vacuo onto silica (20 g). The resulting powder waspurified by flash chromatography on silica, eluting with a gradient of 0to 7% MeOH in DCM. Pure fractions were evaporated to afford the titlecompound4-{4-[(3R)-3-methylmorpholin-4-yl]-6-[1-((R)—S-methylsulfonimidoyl)cyclopropyl]pyrimidin-2-yl}-1H-pyrrolo[2,3-b]pyridine(1.789 g, 39%); ¹H NMR (400 MHz, DMSO-d⁶) 1.27 (3H, d), 1.43 (1H, dd),1.46-1.58 (2H, m), 1.69-1.77 (1H, m), 3.10 (3H, s), 3.27 (1H, td), 3.51(1H, td), 3.66 (1H, dd), 3.80 (1H, d), 3.85 (1H, s), 4.01 (1H, dd), 4.19(1H, d), 4.59 (1H, s), 6.99 (1H, s), 7.22 (1H, dd), 7.54-7.63 (1H, m),7.94 (1H, d), 8.33 (1H, d), 11.80 (1H, s); m/z: (ES+) MH⁺, 413.50.Chiral HPLC: (Kronlab prep system, 20 μm Chiralpak OJ (250 mm×4.6 mm)column eluting with Hexane/EtOH/MeOH/TEA 50/25/25/0.1) Rf, 9.684 99.4%.

The fractions containing the second eluting compound were combined andevaporated. The residue was dissolved in DCM (50 ml) and concentrated invacuo onto silica gel (20 g). The resulting powder was purified byflash<autotext key=“0CA02197” name=“[AP-silica/alumina]” type=“lookup”length=“6”/> chromatography on silica, eluting with a gradient of0<autotext key=“0CA02198” name=“[AP-Num Purification]” type=“lookup”length=“1”/> to 7<autotext key=“0CA02199” name=“[AP-Num Purification]”type=“lookup” length=“1”/>% MeOH<autotext key=“0CA0219A”name=“[AP-Solvents]” type=“lookup” length=“4”/> in DCM<autotextkey=“0CA0219B” name=“[AP-Solvents]” type=“lookup” length=“3”/>. Purefractions were evaporated to afford the title compound4-{4-[(3R)-3-Methylmorpholin-4-yl]-6-[1-((S)—S-methylsulfonimidoyl)cyclopropyl]pyrimidin-2-yl}-1H-pyrrolo[2,3-b]pyridine(2.85 g, 62%); ¹H NMR (400 MHz, DMSO-d⁶) 1.27 (3H, d), 1.38-1.46 (1H,dd), 1.51 (2H, m), 1.72-1.81 (1H, m), 3.10 (3H, s), 3.26 (1H, td), 3.51(1H, td), 3.66 (1H, dd), 3.80 (1H, d), 3.84 (1H, s), 3.94-4.04 (1H, dd),4.21 (1H, d), 4.56 (1H, s), 6.99 (1H, s), 7.22 (1H, dd), 7.53-7.63 (1H,m), 7.94 (1H, d), 8.33 (1H, d), 11.80 (1H, s); m/z: (ES+) MH⁺, 413.53.Chiral HPLC: (Kronlab prep system, 20 μm Chiralpak OJ (250 mm×4.6 mm)column eluting with Hexane/EtOH/MeOH/TEA 50/25/25/0.1) Rf, 18.287 99.3%.

Example 2.02 can also be prepared as follows

Dichlorobis(triphenylphosphine)palladium(II) (2.59 mg, 3.69 gmol) wasadded in one portion to(3R)-4-(2-chloro-6-(1-((R)—S-methylsulfonimidoyl)cyclopropyl)pyrimidin-4-yl)-3-methylmorpholine(63 mg, 0.15 mmol), 2M aqueous Na₂CO₃ solution (0.089 ml, 0.18 mmol) and4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine(58.8 mg, 0.15 mmol) in DME:water 4:1 (5 ml) at RT. The reaction mixturewas stirred at 90° C. for 4 hours. Sodium hydroxide, 2M aqueous solution(0.131 ml, 0.26 mmol) was added and the mixture was heated at 50° C. for18 hours. The reaction mixture was acidified with 2M HCl to pH7. Thereaction mixture was filtered and then purified by preparative HPLCusing decreasingly polar mixtures of water (containing 1% NH₃) and MeCNas eluents. Pure fractions were evaporated and the residue trituratedwith isohexane and Et₂O to give a solid which was collected byfiltration and dried under vacuum to afford the title compound (44.0 mg,71%); ¹H NMR (400 MHz, DMSO-d⁶) 1.29 (3H, d), 1.40-1.61 (3H, m),1.70-1.81 (1H, m), 3.10 (3H, d), 3.53 (1H, dd), 3.68 (1H, dd), 3.77-3.87(2H, m), 4.02 (1H, dd), 4.19 (1H, d), 4.58 (1H, s), 7.01 (1H, d), 7.23(1H, dd), 7.55-7.61 (1H, m), 7.95 (1H, d), 8.34 (1H, d), 11.75 (1H, s).;m/z: (ES+) MH⁺, 413.19. Chiral HPLC: (HP1100 System 4, 5 μm ChiralcelOJ-H (250 mm×4.6 mm) column eluting with iso-Hexane/EtOH/MeOH/TEA50/25/25/0.1) Rf, 9.023 88.0%, 15.796 12.0%.

The(3R)-4-(2-chloro-6-(1-((R)—S-methylsulfonimidoyl)cyclopropyl)pyrimidin-4-yl)-3-methylmorpholine,used as starting material, can be prepared as follows:

Sodium hydroxide (Sigma-Aldrich 415413, d=1.515 g/ml, 155 ml of a 50%solution, 2902.66 mmol) was added toN-[({2-chloro-6-[(3R)-3-methylmorpholin-4-yl]pyrimidin-4-yl}methyl)(methyl)oxido-λ6-(R)-sulfanylidene]-2,2,2-trifluoroacetamide(19.39 g, 48.38 mmol), 1,2-dibromoethane (16.68 mL, 193.51 mmol) andtetraoctylammonium bromide (2.65 g, 4.84 mmol) in methyl THF (1000 ml)at 20° C. under nitrogen. The resulting mixture was stirred at 20° C.for 24 hours. The reaction mixture was diluted with methyl THF (1000 ml)and the aqueous layer separated. The organic layer was diluted furtherwith EtOAc (1000 ml) and then washed with water (1500 ml). The organiclayer was dried over MgSO₄, filtered and evaporated. The residue waspurified by flash chromatography on silica, eluting with a gradient of 0to 5% MeOH in DCM. Pure fractions were evaporated to dryness to afford(3R)-4-(2-chloro-6-(1-((R)—S-methylsulfonimidoyl)cyclopropyl)pyrimidin-4-yl)-3-methylmorpholine(6.88 g, 43%); ¹H NMR (400 MHz, CDCl₃) 1.32 (3H, d), 1.43 (2H, q), 1.72(2H, q), 2.35 (1H, s), 3.09 (3H, s), 3.29 (1H, td), 3.53 (1H, td), 3.67(1H, dd), 3.78 (1H, d), 4.00 (2H, dd), 4.32 (1H, s), 6.79 (1H, s); m/z:(ES+) MH⁺, 331.18 and 333.15.

Example 2.02 can also be prepared as follows:

2M NaOH solution (14.86 ml, 29.72 mmol) was added to(3R)-3-methyl-4-(6-(1-((R)—S-methylsulfonimidoyl)cyclopropyl)-2-(1-tosyl-1H-pyrrolo[2,3-b]pyridin-4-yl)pyrimidin-4-yl)morpholine(8.42 g, 14.86 mmol) in DME:water 4:1 (134 ml). The resulting solutionwas stirred at RT for 4 days. In a separate experiment, 2M NaOH solution(7.06 ml, 14.12 mmol) was added to(3R)-3-methyl-4-(6-(1-((R)—S-methylsulfonimidoyl)cyclopropyl)-2-(1-tosyl-1H-pyrrolo[2,3-b]pyridin-4-yl)pyrimidin-4-yl)morpholine(4 g, 7.06 mmol) in DME:water 4:1 (63.5 ml). The resulting solution wasstirred at RT for 18 hours. The reaction mixtures from the twoprocedures were combined and then neutralised with 2M HCl. The mixturewas evaporated onto reverse phase silica gel (40 g) and the resultingpowder was purified by flash chromatography on reverse phase silica,eluting with a gradient of 20 to 60% ACN in water with 1% ammonia. Purefractions were evaporated to dryness to afford the title compound (7.05g, 78%); ¹H NMR (400 MHz, DMSO-d⁶) 1.27 (3H, t), 1.39-1.6 (3H, m),1.7-1.8 (1H, m), 3.10 (3H, s), 3.26 (1H, d), 3.52 (1H, td), 3.67 (1H,dd), 3.80 (2H, t), 3.97-4.02 (1H, m), δ 4.19 (1H, d), 4.59 (1H, s), 7.00(1H, s), 7.22 (1H, dd), 7.53-7.61 (1H, m), 7.95 (1H, d), 8.33 (1H, d),11.75 (1H, s); m/z: (ES+) MH⁺, 413.08.

The(3R)-3-methyl-4-(6-(1-((R)—S-methylsulfonimidoyl)cyclopropyl)-2-(1-tosyl-1H-pyrrolo[2,3-b]pyridin-4-yl)pyrimidin-4-yl)morpholine,used as starting material, can be prepared as follows:

a) A solution of4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine(21.15 g, 53.11 mmol) in DME (212 ml) was added to a solution of(3R)-4-(2-chloro-6-(1-((R)—S-methylsulfonimidoyl)cyclopropyl)pyrimidin-4-yl)-3-methylmorpholine(12.55 g, 37.93 mmol) in DME:water 4:1 (55 ml). 2M aqueous sodiumcarbonate solution (22.76 ml, 45.52 mmol) anddichlorobis(triphenylphosphine)palladium(II) (0.666 g, 0.95 mmol) wereadded. The resulting solution was stirred at 90° C. for 2 hours undernitrogen. The reaction mixture was diluted with EtOAc (400 ml), andwashed with water (400 ml). The organic layer was dried over MgSO₄,filtered and evaporated. The residue was dissolved in DCM (100 ml) and aportion was purified by flash chromatography on silica eluting with agradient of 0 to 5% MeOH in DCM. Pure fractions were evaporated toafford(3R)-3-methyl-4-(6-(1-((R)—S-methylsulfonimidoyl)cyclopropyl)-2-(1-tosyl-1H-pyrrolo[2,3-b]pyridin-4-yl)pyrimidin-4-yl)morpholine(8.42 g, 39%); ¹H NMR (400 MHz, CDCl₃) 1.36 (3H, d), 1.52 (2H, dd), 1.80(2H, dd), 2.24-2.46 (3H, s), 3.10 (3H, s), 3.36 (1H, td), 3.60 (1H, td),3.74 (1H, dd), 3.84 (1H, d), 3.99-4.18 (2H, m), 4.47 (1H, s), 6.91 (1H,s), 7.23-7.3 (3H, m, obscured by CDCl₃), 7.45 (1H, d), 7.81 (1H, d),8.08 (3H, dd), 8.51 (1H, d); m/z: (ES+) MH⁺, 567.4. The rest of thematerial was evaporated and the residue was dissolved in DCM (500 ml)and concentrated in vacuo onto silica (100 g). The resulting powder waspurified by flash chromatography on silica, eluting with a gradient of 0to 5% MeOH in DCM. Pure fractions were evaporated to dryness to afford(3R)-3-methyl-4-(6-(1-((R)—S-methylsulfonimidoyl)cyclopropyl)-2-(1-tosyl-1H-pyrrolo[2,3-b]pyridin-4-yl)pyrimidin-4-yl)morpholine(4.00 g, 19%); ¹H NMR (400 MHz, DMSO-d⁶) 1.19-1.31 (3H, m), 1.37-1.58(3H, m), 1.75 (1H, ddd), 2.34 (3H, s), 3.04 (3H, d), 3.2-3.27 (1H, m),3.46-3.54 (1H, m), 3.65 (1H, dd), 3.78 (1H, d), 3.82 (1H, s), 3.99 (1H,dd), 4.16 (1H, d), 4.54 (1H, s), 7.04 (1H, s), 7.42 (2H, d), 7.54 (1H,d), 8.01 (3H, dd), 8.10 (1H, d), 8.49 (1H, d); m/z: (ES+) MH⁺, 567.00.

Example 2.02 can also be prepared as follows:

2M NaOH solution (0.2 ml, 0.40 mmol) was added to(3R)-3-methyl-4-(6-(1-((R)—S-methylsulfonimidoyl)cyclopropyl)-2-(1-tosyl-1H-pyrrolo[2,3-b]pyridin-4-yl)pyrimidin-4-yl)morpholine(0.107 g, 0.19 mmol) in DME:water 4:1 (4 ml). The resulting solution wasstirred at 50° C. for 18 hours and then further 2M NaOH solution (0.2ml, 0.40 mmol) was added and the solution was stirred at 50° C. for 3hours. The reaction mixture was evaporated to dryness and the residuedissolved in DCM (10 ml), and then washed with water (10 ml). Theorganic layer was dried over MgSO₄, filtered and then evaporated. Theresidue was purified by preparative HPLC (Waters SunFire column, 5 gsilica, 19 mm diameter, 100 mm length), using decreasingly polarmixtures of water (containing 0.1% formic acid) and MeCN as eluents.Fractions containing the desired compound were evaporated to dryness toafford the title compound (0.026 g, 30%) as the formate salt; ¹H NMR(400 MHz, DMSO-d⁶) 1.28 (3H, d), 1.38-1.47 (1H, m), 1.47-1.57 (2H, m),1.75 (1H, dd), 3.11 (1H, s), 3.28 (1H, dd), 3.52 (1H, dd), 3.67 (1H,dd), 3.81 (1H, d), 3.98-4.04 (1H, m), 4.18 (1H, s), 4.58 (1H, s), 7.00(1H, s), 7.22 (1H, d), 7.59 (1H, d), 7.95 (1H, d), 8.34 (1H, d), 8.41(3H, s), 11.83 (1H, s); m/z: (ES+) MH⁺, 413.11.

Example 2.02 can also be prepared as follows:

Dichlorobis(triphenylphosphine)palladium(II) (0.061 g, 0.09 mmol) wasadded to(3R)-4-(2-chloro-6-(1-((R)—S-methylsulfonimidoyl)cyclopropyl)pyrimidin-4-yl)-3-methylmorpholine(1.15 g, 3.48 mmol), 2M sodium carbonate solution (6.95 ml, 13.90 mmol)and 1H-pyrrolo[2,3-b]pyridin-4-ylboronic acid (1.877 g, 3.48 mmol) undernitrogen. The resulting solution was stirred at 85° C. for 6 hours. Thereaction mixture was diluted with EtOAc (200 ml), and washedsequentially with water (200 ml) and saturated brine (100 ml). Theorganic layer was dried over MgSO₄, filtered and then evaporated ontosilica gel (10 g). The resulting powder was purified by flashchromatography on silica, eluting with a gradient of 0 to 5% MeOH inDCM. Pure fractions were evaporated to afford the title compound (0.660g, 46%); ¹H NMR (400 MHz, CDCl₃) 1.39 (3H, d), 1.53-1.61 (2H, m),1.78-1.84 (2H, m), 2.43 (1H, s), 3.16 (3H, s), 3.39 (1H, td), 3.63 (1H,td), 3.77 (1H, dd), 3.86 (1H, d), 4.07 (1H, dd), 4.17 (1H, d), 4.53 (1H,s), 6.92 (1H, s), 7.34 (1H, dd), 7.41-7.47 (1H, m), 8.06 (1H, d), 8.43(1H, d), 9.60 (1H, s); m/z: (ES+) MH⁺, 413.12. Chiral HPLC: (HP1100System 4, 5 μm Chiralcel OJ-H (250 mm×4.6 mm) column eluting withHeptane/EtOH/MeOH/TEA 50/25/25/0.1) Rf, 8.113 98.9%.

The 1H-pyrrolo[2,3-b]pyridin-4-ylboronic acid, used as startingmaterial, may be prepared as follows:

4-Bromo-1H-pyrrolo[2,3-b]pyridine (0.944 g, 4.79 mmol) in THF (10 ml)was added dropwise to sodium hydride (0.240 g, 5.99 mmol) in THF (10 ml)at 20° C. under nitrogen. The resulting mixture was stirred at 20° C.for 10 minutes. The reaction mixture was cooled to −78° C. andn-butyllithium in hexanes (2.396 mL, 5.99 mmol) was added dropwise over10 minutes and stirred at −78° C. for 10 minutes. Triisopropyl borate(3.32 mL, 14.37 mmol) was added dropwise over 2 minutes and the reactionmixture allowed to warm to RT over 1.5 hours. The reaction mixture wasquenched with water (10 ml) and C18 silica gel was added (10 g) and themixture was concentrated in vacuo. The resultant solid was purified byreverse phase flash silica chromatography, eluting with a gradient of 5to 40% acetonitrile in water. Pure fractions were evaporated to afford1H-pyrrolo[2,3-b]pyridin-4-ylboronic acid (0.590 g, 76%); m/z: (ES+)MH⁺, 162.88.

Example 2.02 can also be prepared as follows:

4-{4-[(3R)-3-Methylmorpholin-4-yl]-6-[1-((R)—S-methylsulfonimidoyl)cyclopropyl]pyrimidin-2-yl}-1H-pyrrolo[2,3-b]pyridine(approximately 10 g, 25 mmol) was suspended in MTBE (500 ml) and stirredat reflux for 2 hours. The suspension was allowed to cool slowly andstirred at RT overnight. The solid was collected by filtration and driedunder vacuum to afford the title compound (7.12 g) as a whitecrystalline solid; ¹H NMR (400 MHz, DMSO-d⁶) 1.28 (3H, d), 1.44 (1H,dd), 1.47-1.58 (2H, m), 1.76 (1H, dt), 3.11 (3H, s), 3.26 (1H, dd), 3.52(1H, td), 3.67 (1H, dd), 3.81 (1H, d), 3.85 (1H, d), 4.02 (1H, dd), 4.20(1H, d), 4.59 (1H, s), 7.00 (1H, s), 7.23 (1H, dd), 7.57-7.62 (1H, m),7.95 (1H, d), 8.34 (1H, d), 11.81 (1H, s); m/z: (ES+) MH⁺, 413.12. Mpt.(Buchi Melting Point B-545) 222° C. Chiral HPLC: (HP1100 System 7, 5 μmChiralcel OJ (250 mm×4.6 mm) column eluting with Heptane/(EtOH/MeOH50/50)/TEA 50/50/0.1) Rf, 9.836 99.8%.

Example 2.03 and Example 2.04N-Methyl-1-{4-[(3R)-3-methylmorpholin-4-yl]-6-[1-((R)—S-methylsulfonimidoyl)cyclopropyl]pyrimidin-2-yl}-1H-benzimidazol-2-amineandN-Methyl-1-{4-[(3R)-3-methylmorpholin-4-yl]-6-[1-((S)—S-methylsulfonimidoyl)cyclopropyl]pyrimidin-2-yl}-1H-benzimidazol-2-amine

Cesium carbonate (942 mg, 2.89 mmol) was added to(3R)-4-(2-chloro-6-(1-(S-methylsulfonimidoyl)cyclopropyl)pyrimidin-4-yl)-3-methylmorpholine(319 mg, 0.96 mmol) and N-methyl-1H-benzo[d]imidazol-2-amine (284 mg,1.93 mmol) in DMA (10 ml). The resulting suspension was stirred at 80°C. for 45 hours. A further portion ofN-methyl-1H-benzo[d]imidazol-2-amine (284 mg, 1.93 mmol), cesiumcarbonate (942 mg, 2.89 mmol) and sodium methanesulfinate (98 mg, 0.96mmol) were added and the suspension was stirred at 80° C. for 70 hours.The reaction mixture was filtered and then evaporated. The residue wasdissolved in EtOAc (250 ml), and washed sequentially with water (250 ml)and saturated brine (75 ml). The organic layer was dried over MgSO₄,filtered and evaporated onto silica gel (5 g). The resulting powder waspurified by flash chromatography on silica, eluting with a gradient of 0to 5% MeOH in DCM. Pure fractions were evaporated and the residue waspurified by preparative chiral chromatography on a Merck 50 mm, 20 μmChiralpak AS column, eluting isocratically with 70% isohexane in IPA(modified with Et3N) as eluent. The fractions containing the desiredcompound were evaporated to afford the title compound:N-Methyl-1-{4-[(3R)-3-methylmorpholin-4-yl]-6-[1-((R)—S-methylsulfonimidoyl)cyclopropyl]pyrimidin-2-yl}-1H-benzimidazol-2-amine(166 mg, 39%) as the first eluting compound; ¹H NMR (400 MHz, DMSO-d⁶)1.29 (3H, d), 1.47 (2H, dq), 1.55-1.66 (1H, m), 1.69-1.89 (1H, m), 3.01(3H, s), 3.04 (3H, d), 3.30-3.39 (1H, m), 3.52 (1H, td), 3.66 (1H, dd),3.80 (1H, d), 3.95 (1H, s), 4.01 (1H, dd), 4.09 (1H, d), 4.51 (1H, s),6.77 (1H, s), 6.97 (1H, t), 7.08 (1H, t), 7.25 (1H, d), 8.08 (1H, d),8.67 (1H, d); m/z: (ES+) MH⁺, 442.09. Chiral HPLC: (HP1100 System 4, 20μm Chiralpak AS (250 mm×4.6 mm) column eluting with iso-Hexane/IPA/TEA70/30/0.1) Rf, 12.219 >99%.

and the title compound:N-Methyl-1-{4-[(3R)-3-methylmorpholin-4-yl]-6-[1-((S)—S-methylsulfonimidoyl)cyclopropyl]pyrimidin-2-yl}-1H-benzimidazol-2-amine(123 mg, 29%) as the second eluting compound; ¹H NMR (400 MHz, DMSO-d⁶)1.33 (3H, t), 1.45-1.61 (2H, m), 1.61-1.68 (1H, m), 1.80-1.89 (1H, m),3.07 (3H, s), 3.09 (3H, d), 3.39 (1H, dd), 3.58 (1H, td), 3.72 (1H, dd),3.86 (1H, d), 4.01 (1H, s), 4.06 (1H, dd), 4.15 (1H, d), 4.55 (1H, s),6.82 (1H, s), 7.03 (1H, t), 7.14 (1H, t), 7.31 (1H, d), 8.14 (1H, d),8.73 (1H, d); m/z: (ES+) MH⁺, 442.09. Chiral HPLC: (HP1100 System 4, 20μm Chiralpak AS (250 mm×4.6 mm) column eluting with iso-Hexane/IPA/TEA70/30/0.1) Rf, 25.093 >99%.

Example 2.03 can also be prepared as follows:

(3R)-4-(2-Chloro-6-(1-((R)—S-methylsulfonimidoyl)cyclopropyl)pyrimidin-4-yl)-3-methylmorpholine(179 mg, 0.54 mmol), N-methyl-1H-benzo[d]imidazol-2-amine (159 mg, 1.08mmol) and cesium carbonate (529 mg, 1.62 mmol) were suspended in DMA (2ml) and sealed into a microwave tube. The reaction mixture was heated to80° C. for 90 minutes in a microwave reactor and then cooled to RT. Thereaction mixture was filtered and then purified by preparative HPLC,using decreasingly polar mixtures of water (containing 1% NH₃) and MeCNas eluents. Fractions containing the desired compound were evaporated toafford a solid (55.0 mg). In an additional procedure:(R)-4-(2-Chloro-6-(1-((R)—S-methylsulfonimidoyl)cyclopropyl)pyrimidin-4-yl)-3-methylmorpholine(89 mg, 0.27 mmol), N-methyl-1H-benzo[d]imidazol-2-amine (79 mg, 0.54mmol) and cesium carbonate (263 mg, 0.81 mmol) were suspended in DMA (2ml) and sealed into a microwave tube. The reaction mixture was heated to80° C. for 5 hours in a microwave reactor and then cooled to RT. Thereaction mixture was filtered, and combined with the solid from theprevious procedure and then purified by preparative HPLC usingdecreasingly polar mixtures of water (containing 1% NH3) and MeCN aseluents. Fractions containing the desired compound were evaporated andthe residue was purified by preparative HPLC using decreasingly polarmixtures of water (containing 0.1% formic acid) and MeCN as eluents.Fractions containing the desired compound were evaporated and theresidue purified again by preparative HPLC using decreasingly polarmixtures of water (containing 1% NH₃) and MeCN as eluents. Fractionscontaining the desired compound were evaporated to afford the titlecompound (38.4 mg, 32%); ¹H NMR (400 MHz, DMSO-d⁶) 1.29 (3H, d), 1.52(3H, m), 1.72-1.86 (1H, m), 3.02 (3H, s), 3.03 (3H, d), 3.26-3.33 (1H,m), 3.52 (1H, t), 3.66 (1H, d), 3.80 (1H, d), 4.01 (2H, m), 4.12 (1H, s,obscured by methanol peak), 4.51 (1H, s), 6.77 (1H, s), 6.98 (1H, t),7.09 (1H, t), 7.25 (1H, d), 8.08 (1H, d), 8.71 (1H, d); m/z: (ES+) MH⁺,442.16. Chiral HPLC: (HP1100 System 4, 20 μm Chiralpak AS (250 mm×4.6mm) column eluting with iso-Hexane/IPA/TEA 70/30/0.1) Rf, 11.984 97.9%.

The N-methyl-1H-benzo[d]imidazol-2-amine, used as starting material, canbe prepared as follows:

2-Chloro-1H-benzo[d]imidazole (20 g, 131.08 mmol) was charged to highpressure autoclave PV10832 (Hastelloy 450 ml) with methylamine (260 mL,131.08 mmol) and sealed on its trolley and the resulting solution heatedto 160° C. in high pressure blast cell 60 for 16 hours. The pressure inthe autoclave reached 11 bar. The solvent was removed under reducedpressure to afford a brown oil. EtOH was added and the solvent againremoved to afford a brown foam. The foam was dissolved in a minimum ofhot acetone. This was then allowed to cool. The resultant solid wasfiltered affording N-methyl-1H-benzo[d]imidazol-2-amine (9.91 g, 51%);¹H NMR (400 MHz, DMSO-d⁶) 2.83 (3H, s), 6.87-7.00 (2H, m), 7.05-7.25(2H, m), 7.49 (1H, s).

Example 2.05 and Example 2.064-{4-[(3R)-3-Methylmorpholin-4-yl]-6-[1-((R)—S-methylsulfonimidoyl)cyclopropyl]pyrimidin-2-yl}-1H-indoleand4-{4-[(3R)-3-methylmorpholin-4-yl]-6-[1-((S)—S-methylsulfonimidoyl)cyclopropyl]pyrimidin-2-yl}-1H-indole

Dichlorobis(triphenylphosphine)palladium(II) (8.49 mg, 0.01 mmol) wasadded in one portion to(3R)-4-(2-chloro-6-(1-(S-methylsulfonimidoyl)cyclopropyl)pyrimidin-4-yl)-3-methylmorpholine(400 mg, 1.21 mmol), 2M aqueous sodium carbonate solution (0.725 ml,1.45 mmol) and 1H-indol-4-ylboronic acid (234 mg, 1.45 mmol) inDME:water 4:1 (8.575 ml) and the mixture was sealed into a microwavetube. The reaction mixture was heated to 110° C. for 1 hour in amicrowave reactor and then cooled to RT. The mixture was diluted withEtOAc (50 ml) and washed sequentially with water (50 ml) and saturatedbrine (50 ml). The organic layer was evaporated and the residue waspurified by flash chromatography on silica, eluting with a gradient of 0to 100% EtOAc in DCM. Pure fractions were evaporated and the residue waspurified by preparative chiral chromatography on a 20 μm Chiralpak IA(50 mm×250 mm) column, eluting isocratically with a 50:50:0.1 mixture ofHexane:EtOH:TEA as eluent. The fractions containing product wereevaporated to afford the title compound:4-{4-[(3R)-3-methylmorpholin-4-yl]-6-[1-((S)—S-methylsulfonimidoyl)cyclopropyl]pyrimidin-2-yl}-1H-indole(43.8 mg, 24%) as the first eluting compound; ¹H NMR (400 MHz, DMSO-d⁶)1.33 (3H, d), 1.49 (1H, dd), 1.52-1.63 (2H, m), 1.75-1.84 (1H, m), 3.16(3H, s), 3.53-3.62 (1H, m), 3.72 (1H, dd), 3.79-3.89 (2H, m), 4.06 (1H,dd), 4.23 (1H, d), 4.65 (1H, s), 6.96 (1H, s), 7.25 (1H, t), 7.37 (1H,s), 7.50 (1H, t), 7.59 (1H, d), 8.09-8.13 (1H, m), 11.27 (1H, s); m/z:(ES+) MH⁺, 412.24. Chiral HPLC: (HP1100 System 4, 20 μm Chiralpak AS(250 mm×4.6 mm) column eluting with Hexane/EtOH/TEA 50/50/0.1) Rf,8.690 >99%. and the title compound:4-{4-[(3R)-3-methylmorpholin-4-yl]-6-[1-((R)—S-methylsulfonimidoyl)cyclopropyl]pyrimidin-2-yl}-1H-indole(93.5 mg, 52%) as the second eluting compound; ¹H NMR (400 MHz, DMSO-d⁶)1.28 (3H, d), 1.41-1.46 (1H, m), 1.50 (2H, td), 1.75 (1H, dd), 3.11 (3H,s), 3.52 (1H, dd), 3.64-3.70 (1H, m), 3.73-3.83 (2H, m), 4.01 (1H, d),4.20 (1H, d), 4.56 (1H, s), 6.89 (1H, s), 7.19 (1H, t), 7.32 (1H, s),7.44 (1H, s), 7.53 (1H, d), 8.04-8.08 (1H, m), 11.22 (1H, s); m/z: (ES+)MH⁺, 412.24. Chiral HPLC: (HP1100 System 4, 20 μm Chiralpak AS (250mm×4.6 mm) column eluting with Hexane/EtOH/TEA 50/50/0.1) Rf, 36.980>99%.

Example 2.06 can also be prepared as follows:

Dichlorobis(triphenylphosphine)palladium(II) (1.994 mg, 2.84 μmol) wasadded in one portion to(3R)-4-(2-chloro-6-(1-((S)—S-methylsulfonimidoyl)cyclopropyl)pyrimidin-4-yl)-3-methylmorpholine(0.094 g, 0.28 mmol), 2M aqueous sodium carbonate solution (0.170 ml,0.34 mmol) and 1H-indol-4-ylboronic acid (0.055 g, 0.34 mmol) inDME:water 4:1 (2.015 ml) and sealed into a microwave tube. The reactionmixture was heated to 110° C. for 1 hour in a microwave reactor and thencooled to RT. The cooled reaction mixture was passed through a PS-Thiolcartridge and then purified by preparative HPLC eluting withdecreasingly polar mixtures of water (containing 0.1% formic acid) andMeCN. Fractions containing the product were evaporated and the residuewas then purified by ion exchange chromatography, using an SCX column.The desired product was eluted from the column using 2M NH₃/MeOH andpure fractions were evaporated to afford the title compound (0.075 g,64%); ¹H NMR (400 MHz, DMSO-d⁶) 1.27 (3H, d), 1.39-1.56 (3H, m),1.69-1.78 (1H, m), 3.10 (3H, d), 3.52 (1H, td), 3.66 (1H, dd), 3.72-3.83(2H, m), 4.00 (1H, dd), 4.20 (1H, d), 4.57 (1H, s), 6.89 (1H, d), 7.18(1H, t), 7.31 (1H, t), 7.43 (1H, t), 7.53 (1H, d), 8.05 (1H, dd), 11.21(1H, s); m/z: (ES+) MH⁺, 412.55. Chiral HPLC: (HP1100 System 4, 5 μmChiralpak AS-H (250 mm×4.6 mm) column eluting with Heptane/EtOH/TEA50/50/0.1) Rf, 4.511 >99%.

The(3R)-4-(2-chloro-6-(1-((S)—S-methylsulfonimidoyl)cyclopropyl)pyrimidin-4-yl)-3-methylmorpholine,used as starting material, can be prepared as follows:

a) Iodobenzene diacetate (78 g, 243.29 mmol) was added to(3R)-4-(2-chloro-6-((S)-methylsulfinylmethyl)pyrimidin-4-yl)-3-methylmorpholine(70.5 g, 243.29 mmol), 2,2,2-trifluoroacetamide (55.0 g, 486.57 mmol),magnesium oxide (39.2 g, 973.15 mmol) and rhodium(II) acetate dimer(2.69 g, 6.08 mmol) in DCM (2433 ml) under air. The resulting suspensionwas stirred at 20° C. for 24 hours. Further 2,2,2-trifluoroacetamide(13.75 g, 121.64 mmol), magnesium oxide (9.81 g, 243.29 mmol),iodobenzene diacetate (19.59 g, 60.82 mmol) and rhodium(II) acetatedimer (0.672 g, 1.52 mmol) were added and the suspension was stirred at20° C. for 1 day. The reaction mixture was filtered and then silica gel(200 g) added to the filtrate and the solvent removed in vacuo. Theresulting powder was purified by flash chromatography on silica, elutingwith a gradient of 20 to 50% EtOAc in heptane. Pure fractions wereconcentrated and the resultant precipitate collected by filtration toaffordN—[({2-chloro-6-[(3R)-3-methylmorpholin-4-yl]pyrimidin-4-yl}methyl)(methyl)oxido-X6-sulfanylidene]-2,2,2-trifluoroacetamideas a 7:1 mixture of S:R isomers (26.14 g, 27%); ¹H NMR (400 MHz, CDCl₃)1.33 (3H, d), 3.28 (1H, dd), 3.42 (3H, d), 3.46-3.57 (1H, m), 3.61-3.70(1H, m), 3.79 (1H, d), 4.02 (1H, dd), 4.65 (1H, d), 4.85 (1H, dd), 6.49(1H, d); m/z: (ES+) MH⁺, 400.94 and 402.85. Chiral HPLC: (HP1100 System4, 5 μm Chiralpak AD-H (250 mm×4.6 mm) column eluting with Heptane/EtOH50/50) Rf, 4.367 12.5%, 6.053 87.5%. The mother liquers wereconcentrated in vacuo to yield a colourless gum. The gum was trituratedwith isohexane to give a solid which was collected by filtration anddried under vacuum to affordN-[({2-chloro-6-[(3R)-3-methylmorpholin-4-yl]pyrimidin-4-yl}methyl)(methyl)oxido-λ6-sulfanylidene]-2,2,2-trifluoroacetamideas a 2.8:1 mixture of R: S isomers (47.1 g, 48%); ¹H NMR (400 MHz,CDCl₃) 1.33 (3H, d), 3.31 (1H, t), 3.42 (3H, d), 3.47-3.57 (1H, m),3.62-3.70 (1H, m), 3.79 (1H, d), 4.02 (1H, dd), 4.65 (1H, dd), 4.86 (1H,dd), 6.49 (1H, d); m/z: (ES+) MH⁺, 400.94 and 402.86. Chiral HPLC:(HP1100 System 4, 5 μm Chiralpak AD-H (250 mm×4.6 mm) column elutingwith Heptane/EtOH 50/50) Rf, 4.365 73.5%, 6.067 26.4%.b) Cesium hydroxide-hydrate (0.390 g, 3.43 mmol) was added to a 7:1mixture of S:R isomers ofN-[({2-chloro-6-[(3R)-3-methylmorpholin-4-yl]pyrimidin-4-yl}methyl)(methyl)oxido-λ6-sulfanylidene]-2,2,2-trifluoroacetamide(0.209 g, 0.69 mmol), 1,2-dibromoethane (0.236 ml, 2.74 mmol) andtetraoctylammonium bromide (0.037 g, 0.07 mmol) in methyl THF (2 ml) at20° C. under nitrogen. The resulting mixture was stirred at 20° C. for16 hours. Further 1,2-dibromoethane (0.236 mL, 2.74 mmol) was added andthe mixture was stirred at 20° C. for 24 hours. A second portion ofcesium hydroxide-hydrate (0.390 g, 3.43 mmol) was added and the mixturestirred over a weekend. The reaction mixture was filtered and silica gel(5 g) added to the filtrate. The mixture was concentrated in vacuo andthe resultant powder was then purified by flash chromatography onsilica, eluting with a gradient of 0 to 5% MeOH in DCM. Pure fractionswere evaporated to afford(3R)-4-(2-chloro-6-(1-((S)—S-methylsulfonimidoyl)cyclopropyl)pyrimidin-4-yl)-3-methylmorpholine(0.099 g, 44%); ¹H NMR (400 MHz, CDCl₃) 1.31 (3H, t), 1.43 (2H, h),1.67-1.75 (2H, m), 2.33 (1H, s), 3.09 (3H, s), 3.29 (1H, td), 3.53 (1H,td), 3.67 (1H, dd), 3.78 (1H, d), 4.00 (2H, dd+broad s), 4.33 (1H, s),6.78 (1H, s); m/z: (ES+) MH⁺, 331.04 and 332.99. Chiral HPLC: (HP1100System 4, 5 μm Chiralpak AD-H (250 mm×4.6 mm) column eluting withHeptane/IPA/TEA 70/30/0.1) Rf, 5.948 89.5%.]

Example 2.07 and example 2.081-{4-[(3R)-3-Methylmorpholin-4-yl]-6-[1-((R)—S-methylsulfonimidoyl)cyclopropyl]pyrimidin-2-yl}-1H-benzimidazol-2-amineand1-{4-[(3R)-3-methylmorpholin-4-yl]-6-[1-((S)—S-methylsulfonimidoyl)cyclopropyl]pyrimidin-2-yl}-1H-benzimidazol-2-amine

Cesium carbonate (1.773 g, 5.44 mmol) was added to(3R)-4-(2-chloro-6-(1-(S-methylsulfonimidoyl)cyclopropyl)pyrimidin-4-yl)-3-methylmorpholine(0.3 g, 0.91 mmol) and 1H-benzo[d]imidazol-2-amine (0.121 g, 0.91 mmol)in DMA (9.07 ml). The resulting suspension was stirred at 80° C. for 3days. The reaction mixture was evaporated and the residue was dissolvedin EtOAc (500 mL), and the mixture was then washed sequentially withwater (400 mL) and saturated brine (100 mL). The aqueous layer waswashed with EtOAc (4×500 mL). The organic layers were combined and thendried over MgSO₄, filtered and evaporated. The residue was dissolved inDCM (100 mL) and the resulting solution was purified by flashchromatography on silica, eluting with a gradient of 0 to 15% MeOH inDCM. Pure fractions were evaporated and the residue was purified bypreparative chiral chromatography on a 20 μm Chiralpak IA (50 mm×250 mm)column, eluting isocratically with 50:50:0.2:0.1 mixture ofHexane:IPA:AcOH:TEA as eluents. Fractions containing product wereevaporated to afford the first eluted title compound (0.045 g, 23%); ¹HNMR (400 MHz, DMSO-d⁶) 1.29 (3H, d), 1.40-1.49 (2H, m), 1.50-1.58 (1H,m), 1.71-1.84 (1H, m), 3.02 (3H, s), 3.52 (1H, t), 3.67 (1H, d), 3.80(1H, d), 3.93 (1H, s), 4.01 (1H, d), 4.09 (1H, s), 4.48 (1H, s), 6.87(1H, s), 6.97 (1H, dd), 7.07 (1H, dd), 7.18 (1H, d), 7.65 (2H, s), 8.08(1H, d); m/z: (ES+) MH⁺, 428.10. Chiral HPLC: (HP1100 System 3, 20 μmChiralpak IA (250 mm×4.6 mm) column eluting with Hexane/IPA/AcOH/TEA50/50/0.2/0.1) Rf, 5.653 93.8%. and the second eluted title compound(0.030 g, 15%); ¹H NMR (400 MHz, DMSO-d⁶) 1.30 (3H, d), 1.44 (2H, s),1.50-1.58 (1H, m), 1.72-1.82 (1H, m), 3.01 (3H, s), 3.47-3.57 (1H, m),3.63-3.70 (1H, m), 3.78 (1H, s), 3.94 (1H, s), 3.97-4.05 (1H, m),4.04-4.13 (1H, m), 4.43-4.55 (1H, m), 6.88 (1H, s), 6.98 (1H, d), 7.07(1H, s), 7.18 (1H, d), 7.66 (2H, s), 8.07 (1H, d).; m/z: (ES+) MH⁺,428.10. Chiral HPLC: (HP1100 System 4, 20 μm Chiralpak IA (250 mm×4.6mm) column eluting with Hexane/IPA/AcOH/TEA 50/50/0.2/0.1) Rf, 7.03196.9%.

Example 2.09 and Example 2.104-Fluoro-N-methyl-1-{4-[(3R)-3-methylmorpholin-4-yl]-6-[1-((R)—S-methylsulfonimidoyl)cyclopropyl]pyrimidin-2-yl}-1H-benzimidazol-2-amineand4-fluoro-N-methyl-1-{4-[(3R)-3-methylmorpholin-4-yl]-6-[1-((S)—S-methylsulfonimidoyl)cyclopropyl]pyrimidin-2-yl}-1H-benzimidazol-2-amine

Cesium carbonate (1.891 g, 5.80 mmol) was added to(3R)-4-(2-chloro-6-(1-(S-methylsulfonimidoyl)cyclopropyl)pyrimidin-4-yl)-3-methylmorpholine(0.64 g, 1.93 mmol) and 7-fluoro-N-methyl-1H-benzo[d]imidazol-2-amine(0.639 g, 3.87 mmol) in DMA (20.15 ml). The resulting suspension wasstirred at 80° C. for 45 hours. Further portions of7-fluoro-N-methyl-1H-benzo[d]imidazol-2-amine (0.639 g, 3.87 mmol),cesium carbonate (1.891 g, 5.80 mmol) and sodium methanesulfinate (0.197g, 1.93 mmol) were added and the suspension was stirred at 80° C. for afurther 70 hours. The reaction mixture was filtered and the filtrate wasdiluted with EtOAc (250 mL) and then washed sequentially with water (250mL) and saturated brine (75 mL). The organic layer was dried over MgSO₄,filtered and then evaporated directly onto silica (5 g). The resultingpowder was purified by flash chromatography on silica, eluting with agradient of 0 to 5% MeOH in DCM. Pure fractions were evaporated and theresidue was purified by preparative chiral HPLC on a 20 μm Chiralpak IA(50 mm×250 mm) column eluting with a 50:50:0.2:0.1 mixture ofHexane:IPA:AcOH:TEA as eluents. Fractions containing product wereevaporated to afford the first eluting title compound (0.138 g, 16%); ¹HNMR (400 MHz, DMSO-d₆) 1.30 (3H, d), 1.50 (2H, dd), 1.60 (1H, d), 1.80(1H, s), 3.01 (3H, s), 3.06 (3H, d), 3.33 (1H, d), 3.51 (1H, d), 3.66(1H, d), 3.80 (1H, d), 3.99 (1H, s), 4.02 (1H, s), 4.08 (1H, s), 4.50(1H, s), 6.79 (1H, s), 6.96 (2H, dd), 7.92 (1H, d), 8.79 (1H, d); m/z:(ES+) MH⁺, 460.08. Chiral HPLC: (HP1100 System 4, 20 μm Chiralpak AS(250 mm×4.6 mm) column eluting with Heptane/IPA/TEA 70/30/0.1) Rf,10.697 >99%. and the second eluting title compound (0.183 g, 21%); ¹HNMR (400 MHz, DMSO-d⁶) 1.29 (3H, d), 1.50 (2H, d), 1.59 (1H, d), 1.79(1H, s), 3.02 (3H, s), 3.06 (3H, d), 3.33 (1H, d), 3.52 (1H, t), 3.67(1H, d), 3.80 (1H, d), 3.98 (1H, s), 4.01 (1H, d), 4.08 (1H, s), 4.50(1H, s), 6.79 (1H, s), 6.96 (2H, dd), 7.92 (1H, d), 8.79 (1H, d); m/z:(ES+) MH⁺, 460.08. Chiral HPLC: (HP1100 System 4, 20 μm Chiralpak AS(250 mm×4.6 mm) column eluting with Heptane/IPA/TEA 70/30/0.1) Rf,18.427 99.8%.

The 7-fluoro-N-methyl-1H-benzo[d]imidazol-2-amine, used as startingmaterial, was prepared as follows:

a) 3-Fluorobenzene-1,2-diamine (0.600 g, 4.76 mmol) was dissolved in THF(14.82 ml) and 1,1′-carbonyldiimidazole (0.848 g, 5.23 mmol) was addedat RT. The reaction mixture was stirred overnight at RT and then heatedfor 24 hours at 50° C. The mixture was cooled to RT and ammonia in MeOH(1.5 ml) was added and the mixture stirred for 30 minutes. The mixturewas diluted with water (40 ml) and the resultant brown solid wascollected by filtration, washed with water and then dried in vacuo toafford 4-fluoro-1H-benzo[d]imidazol-2(3H)-one (0.700 g, 97%) which wasused in the next step without further purification; ¹H NMR (400 MHz,DMSO-d⁶) 6.81 (2H, ddd), 6.88-6.95 (1H, m), 10.82 (1H, s), 11.08 (1H,s); m/z: (ES−) M−H⁻, 151.19.b) A solution of 4-fluoro-1H-benzo[d]imidazol-2(3H)-one (0.7 g, 4.60mmol) in phosphorus oxychloride (14.11 ml, 151.39 mmol) was heated at100° C. for 18 hours. The reaction mixture was cooled to RT and excessphosphorus oxychloride was evaporated in vacuo. The residue wasneutralized slowly (Care: exotherm) with saturated sodium bicarbonatesolution (10 ml), and the mixture was then extracted with EtOAc (3×20ml). The combined organic layers were washed with saturated brine andthen dried over Na₂SO₄, filtered and evaporated to afford2-chloro-7-fluoro-1H-benzo[d]imidazole (0.740 g, 94%) which was used inthe next step without further purification; ¹H NMR (400 MHz, DMSO-d⁶)7.01-7.11 (1H, m), 7.23 (1H, td), 7.32 (1H, s), 13.59 (1H, s); m/z:(ES+) MH⁺, 171.20.c) 2-Chloro-7-fluoro-1H-benzo[d]imidazole (1.7 g, 9.97 mmol) was chargedto a high pressure autoclave PV10832 (Parr 160 ml) with methylamine (40%EtOH solution, 50 ml, 9.97 mmol) and sealed on its trolley and theresulting solution heated to 160° C. in high pressure blast cell 60 for16 hours. The pressure in the autoclave reached 13 bar. The mixture wasevaporated and the residue dissolved in MeOH and then added to an SCXcolumn. The column was eluted with 7N ammonia in MeOH and fractionscontaining product were evaporated to leave a brown oil. The oil waspurified by flash chromatography on silica, eluting with a gradient of 5to 20% MeOH in DCM. Pure fractions were evaporated to afford7-fluoro-N-methyl-1H-benzo[d]imidazol-2-amine (1.230 g, 75%); ¹H NMR(400 MHz, DMSO-d⁶) 2.88 (3H, d), 6.54 (1H, bs), 6.67-6.73 (1H, m), 6.81(1H, dd), 6.95 (1H, d); m/z: (ES+) MH⁺, 166.00.

Example 2.114-{4-[(3R)-3-Methylmorpholin-4-yl]-6-[1-(S-methylsulfonimidoyl)cyclopropyl]pyrimidin-2-yl}-1H-pyrrolo[2,3-c]pyridine

Tert-butyl4-(4-((R)-3-methylmorpholino)-6-(1-(S-methylsulfonimidoyl)cyclopropyl)pyrimidin-2-yl)-1H-pyrrolo[2,3-c]pyridine-1-carboxylate(0.223 g, 0.44 mmol) was added to TFA (5 ml) and DCM (5.00 ml). Theresulting solution was stirred at RT for 1 hour. The reaction mixturewas evaporated and the residue was purified by preparative HPLC usingdecreasingly polar mixtures of water (containing 1% NH₃) and MeCN aseluents. Fractions containing the desired compound were evaporated andthe residue was triturated with Et₂O to give a solid which was collectedby filtration and dried under vacuum to afford the title compound (0.086g, 48%); ¹H NMR (400 MHz, DMSO-d⁶) 1.29 (3H, d), 1.40-1.60 (3H, m), 1.76(1H, d), 3.11 (3H, s), 3.12-3.21 (1H, m), 3.53 (1H, t), 3.68 (1H, d),3.80 (2H, d), 4.01 (1H, d), 4.20 (1H, s), 4.58 (1H, s), 6.95 (1H, d),7.28 (1H, s), 7.71 (1H, s), 8.83 (1H, s), 9.08 (1H, s), 11.75 (1H, s);m/z: (ES+) MH⁺, 413.16.

The tert-butyl4-(4-((R)-3-methylmorpholino)-6-(1-(S-methylsulfonimidoyl)cyclopropyl)pyrimidin-2-yl)-1H-pyrrolo[2,3-c]pyridine-1-carboxylate,used as starting material, was prepared as follows:

1,1′-Bis(diphenylphosphino)ferrocenedichloropalladium(II) (0.906 g, 1.25mmol) was added to tert-butyl4-bromo-1H-pyrrolo[2,3-c]pyridine-1-carboxylate (1.24 g, 4.17 mmol),potassium acetate (2.87 g, 29.21 mmol) and bis(pinacolato)diboron (4.73g, 18.63 mmol) in dioxane (100 ml) under nitrogen. The resultingsolution was stirred at reflux for 3 days to afford an approximate 2:1mixture of boc to de-boc product. To this mixture was addeddichlorobis(triphenylphosphine)palladium(II) (0.017 g, 0.02 mmol),(3R)-4-(2-chloro-6-(1-(S-methylsulfonimidoyl)cyclopropyl)pyrimidin-4-yl)-3-methylmorpholine(0.318 g, 0.96 mmol), 2M aqueous sodium carbonate solution (0.577 mL,1.15 mmol) under nitrogen. The reaction mixture was stirred at 90° C.for 6 hours. The reaction mixture was concentrated, diluted with EtOAc(400 ml), and then washed sequentially with water (300 ml) and saturatedbrine (75 ml). The organic layer was dried over MgSO₄, filtered and thenevaporated directly onto silica (30 g). The resulting powder waspurified by flash chromatography on silica, eluting with a gradient of 0to 5% MeOH in DCM. Pure fractions were evaporated to dryness to affordtert-butyl4-(4-((R)-3-methylmorpholino)-6-(1-(S-methylsulfonimidoyl)cyclopropyl)pyrimidin-2-yl)-1H-pyrrolo[2,3-c]pyridine-1-carboxylate(0.227 g, 46%); ¹H NMR (400 MHz, DMSO-d⁶) 1.28 (3H, d), 1.40-1.61 (3H,m), 1.68 (9H, s), 1.76 (1H, dd), 3.09 (3H, d), 3.24 (1H, m), 3.52 (1H,t), 3.67 (1H, dd), 3.79 (2H, d), 4.00 (1H, dd), 4.19 (1H, s), 4.56 (1H,s), 7.00 (1H, d), 7.57 (1H, d), 8.00 (1H, d), 9.25 (1H, s), 9.37 (1H,s); m/z: (ES+) MH⁺, 513.19.

Example 3.01 and Example 3.02N-methyl-1-{4-[1-methyl-1-((S)—S-methylsulfonimidoyl)ethyl]-6-[(3R)-3-methylmorpholin-4-yl]pyrimidin-2-yl}-1H-benzimidazol-2-amineandN-methyl-1-{4-[1-methyl-1-((R)—S-methylsulfonimidoyl)ethyl]-6-[(3R)-3-methylmorpholin-4-yl]pyrimidin-2-yl}-1H-benzimidazol-2-amine

Cesium carbonate (3.19 g, 9.79 mmol) was added toN-[(2-{2-chloro-6-[(3R)-3-methylmorpholin-4-yl]pyrimidin-4-yl}propan-2-yl)(methyl)oxido-λ6-sulfanylidene]-2,2,2-trifluoroacetamide(0.7 g, 1.63 mmol) and N-methyl-1H-benzo[d]imidazol-2-amine (0.360 g,2.45 mmol) in DMA (10 ml). The resulting suspension was stirred at 80°C. for 5 hours. The reaction mixture was filtered and then concentratedin vacuo. The residue was purified by preparative HPLC, usingdecreasingly polar mixtures of water (containing 1% NH₃) and MeCN aseluents. Fractions containing the desired compound were evaporated todryness and the residue was purified by preparative chiral HPLC on aMerck 50 mm, 20 μm ChiralCel OJ column, eluting isocratically with 20%EtOH in isohexane (modified with Et₃N) as eluent. Fractions containingthe first eluting compound, were evaporated and the residue dissolved inDCM (20 ml) and then evaporated onto silica (1 g). The resulting powderwas purified by flash chromatography on silica, eluting with a gradientof 0 to 7% MeOH in DCM. Pure fractions were evaporated to afford thetitle compound:N-methyl-1-{4-[1-methyl-1-((R)—S-methylsulfonimidoyl)ethyl]-6-[(3R)-3-methylmorpholin-4-yl]pyrimidin-2-yl}-1H-benzimidazol-2-amine(66.3 mg, 36%); ¹H NMR (400 MHz, DMSO-d⁶) 1.30 (3H, d), 1.76 (6H, d),2.78 (3H, d), 3.03 (3H, d), 3.33-3.41 (1H, m), 3.47-3.58 (1H, m), 3.68(1H, dd), 3.81 (1H, d), 3.89 (1H, s), 4.02 (1H, dd), 4.12 (1H, d), 4.53(1H, s), 6.80 (1H, s), 6.98 (1H, dd), 7.08 (1H, t), 7.24 (1H, d), 8.10(1H, d), 8.69 (1H, d); m/z: (ES+) MH⁺, 444.18. Chiral HPLC: (HP1100System 5, 20 μm Chiralcel OJ (250 mm×4.6 mm) column eluting withiso-Hexane/EtOH/TEA 80/20/0.1) Rf, 21.886 >99%.

Fractions containing the second eluting compound were evaporated and theresidue dissolved in DCM (20 ml) and then evaporated onto silica gel (1g). The resulting powder was purified by flash chromatography on silica,eluting with a gradient of 0 to 7% MeOH in DCM. Pure fractions wereevaporated to afford the title compound:N-methyl-1-{4-[1-methyl-1-((S)—S-methylsulfonimidoyl)ethyl]-6-[(3R)-3-methylmorpholin-4-yl]pyrimidin-2-yl}-1H-benzimidazol-2-amine(62.4 mg, 34%); ¹H NMR (400 MHz, DMSO-d⁶) 1.31 (3H, d), 1.76 (6H, d),2.78 (3H, d), 3.03 (3H, d), 3.33-3.39 (1H, m), 3.54 (1H, td), 3.68 (1H,dd), 3.81 (1H, d), 3.88 (1H, s), 4.02 (1H, dd), 4.12 (1H, d), 4.53 (1H,s), 6.80 (1H, s), 6.92-7.01 (1H, m), 7.08 (1H, td), 7.24 (1H, d), 8.10(1H, d), 8.69 (1H, d); m/z: (ES+) MH⁺, 444.15. Chiral HPLC: (HP1100System 5, 20 μm Chiralcel OJ (250 mm×4.6 mm) column eluting withiso-Hexane/EtOH/TEA 80/20/0.1) Rf, 34.353 99.4%.

TheN-[(2-{2-chloro-6-[(3R)-3-methylmorpholin-4-yl]pyrimidin-4-yl}propan-2-yl)(methyl)oxido-λ6-sulfanylidene]-2,2,2-trifluoroacetamide,used as starting material, was prepared as follows:

a)(3R)-4-(2-Chloro-6-(methylsulfinylmethyl)pyrimidin-4-yl)-3-methylmorpholine(1.75 g, 6.04 mmol) was dissolved in DMF (34.6 ml), to this was addedslowly NaH (0.604 g, 15.10 mmol) and the reaction mixture was stirredfor 5 minutes at RT. To the mixture was rapidly added methyl iodide(0.944 ml, 15.10 mmol) and the mixture was stirred for 1 hour. Thereaction mixture was quenched with saturated NH₄Cl solution (50 mL),extracted with DCM (3×50 mL) and the combined organic layers were passedthrough a phase separating column and then evaporated to afford a yellowgum. Water (50 mL) was added to the gum and the mixture extracted withEtOAc (3×50 mL). The combined organic layers were dried over MgSO₄,filtered and then evaporated. The residue was purified by flashchromatography on silica, eluting with a gradient of 0 to 3% MeOH inDCM. Pure fractions were evaporated to afford(3R)-4-(2-chloro-6-(2-(methylsulfinyl)propan-2-yl)pyrimidin-4-yl)-3-methylmorpholine(1.693 g, 88%); ¹H NMR (400 MHz, DMSO-d⁶) 1.19 (3H, d), 1.49 (6H, dd),2.17 (3H, t), 3.19 (1H, dd), 3.37-3.48 (1H, m), 3.57 (1H, dd), 3.71 (1H,d), 3.92 (1H, d), 4.03 (1H, s), 4.41 (1H, s), 6.70 (1H, s); m/z: (ES+)MH⁺, 318.09 and 320.04.b) Iodobenzene diacetate (1.716 g, 5.33 mmol) was added to(3R)-4-(2-chloro-6-(2-(methylsulfinyl)propan-2-yl)pyrimidin-4-yl)-3-methylmorpholine(1.693 g, 5.33 mmol), magnesium oxide (0.859 g, 21.31 mmol),2,2,2-trifluoroacetamide (1.204 g, 10.65 mmol) and rhodium(II) acetatedimer (0.059 g, 0.13 mmol) in DCM (100 mL). The resulting suspension wasstirred at RT for 18 hours. The reaction mixture was filtered throughCelite and then concentrated in vacuo onto silica (15 g). The resultingpowder was purified by flash chromatography on silica, eluting with agradient of 0 to 10% MeOH in DCM. Pure fractions were evaporated toaffordN-[(2-{2-chloro-6-[(3R)-3-methylmorpholin-4-yl]pyrimidin-4-yl}propan-2-yl)(methyl)oxido-λ6-sulfanylidene]-2,2,2-trifluoroacetamide(0.700 g, 31%); ¹H NMR (400 MHz, DMSO-d⁶) 1.20 (3H, dd), 1.83 (6H, d),3.20 (1H, dd), 3.41 (1H, dddd), 3.56 (1H, d), 3.59 (3H, d), 3.72 (1H,d), 3.94 (1H, dd), 4.07 (1H, s), 4.45 (1H, s), 6.93 (1H, d); m/z: (ES+)MH⁺, 429.4 and 431.5.

Example 4.01 and example 4.02N-Methyl-1-{4-[(3R)-3-methylmorpholin-4-yl]-6-[4-((S)—S-methylsulfonimidoyl)tetrahydro-2H-pyran-4-yl]pyrimidin-2-yl}-1H-benzimidazol-2-amineandN-methyl-1-{4-[(3R)-3-methylmorpholin-4-yl]-6-[4-((R)—S-methylsulfonimidoyl)tetrahydro-2H-pyran-4-yl]pyrimidin-2-yl}-1H-benzimidazol-2-amine

Cesium carbonate (2.076 g, 6.37 mmol) was added toN-[(4-{2-chloro-6-[(3R)-3-methylmorpholin-4-yl]pyrimidin-4-yl}tetrahydro-2H-pyran-4-yl)(methyl)oxido-λ6-sulfanylidene]-2,2,2-trifluoroacetamide(1.00 g, 2.12 mmol), sodium methanesulfinate (0.217 g, 2.12 mmol) andN-methyl-1H-benzo[d]imidazol-2-amine (0.313 g, 2.12 mmol) in DMA (20ml). The resulting suspension was stirred at 80° C. for 18 hours. Thereaction mixture was filtered and then evaporated. The residue wasdissolved in EtOAc (100 mL) and washed sequentially with water (100 mL)and then with saturated brine (10 mL). The aqueous layer was washed withEtOAc (2×100 mL). The organic layers were combined, dried over MgSO₄,filtered and then evaporated. The residue was purified by flashchromatography on silica, eluting with a gradient of 0 to 7% MeOH inDCM. Fractions containing product were evaporated and the residue waspurified by preparative chiral HPLC on a ChiralCel OD column, elutingisocratically with 50% hexane in EtOH (modified with Et₃N) as eluent.Fractions containing isomer 1, eluted first, were evaporated and theresidue dissolved in DCM (10 ml) and then evaporated onto silica (0.5g). The resulting powder was purified by flash chromatography on silica,eluting with a gradient of 0 to 7% MeOH in DCM. Pure fractions wereevaporated to dryness to afford isomer 1 (58.0 mg, 36%); ¹H NMR (400MHz, DMSO-d⁶) 1.31 (3H, d), 2.19-2.35 (2H, m), 2.65-2.75 (5H, m), 3.02(2H, d), 3.24 (2H, dd), 3.33-3.39 (1H, m), 3.56 (1H, td), 3.71 (1H, dd),3.81 (1H, d), 3.87-3.97 (2H, m), 4.03 (1H, dd), 4.06 (1H, s), 4.16 (1H,d), 4.53 (1H, s), 6.90 (1H, s), 6.99 (1H, td), 7.09 (1H, td), 7.26 (1H,dd), 8.06 (1H, d), 8.39 (1H, q); m/z: (ES+) MH⁺, 486.53. Chiral HPLC:(HP1100 System 4, 20 μm Chiralpak OJ (250 mm×4.6 mm) column eluting withHexane/EtOH/TEA 50/50/0.1) Rf, 8.874 >99%.

Fractions containing isomer 2, eluted second, were evaporated and theresidue dissolved in DCM (10 mL) and then evaporated onto silica gel(0.5 g). The resulting powder was purified by flash chromatography onsilica, eluting with a gradient of 0 to 7% MeOH in DCM. Pure fractionswere evaporated to afford isomer 2 (71.8 mg, 44%); ¹H NMR (400 MHz,DMSO-d⁶) 1.30 (3H, d), 2.19-2.36 (2H, m), 2.61-2.76 (5H, m), 3.02 (3H,d), 3.18-3.27 (2H, m), 3.36 (1H, dd), 3.56 (1H, td), 3.71 (1H, dd), 3.81(1H, d), 3.93 (2H, dd), 4.00-4.08 (2H, m), 4.17 (1H, d), 4.52 (1H, s),6.91 (1H, s), 6.99 (1H, td), 7.09 (1H, td), 7.26 (1H, d), 8.06 (1H, d),8.39 (1H, q); m/z: (ES+) MH⁺, 486.57. Chiral HPLC: (HP1100 System 4, 20μm Chiralpak OJ (250 mm×4.6 mm) column eluting with Hexane/EtOH/TEA50/50/0.1) Rf, 12.742 >99%.

TheN-[(4-{2-chloro-6-[(3R)-3-methylmorpholin-4-yl]pyrimidin-4-yl}tetrahydro-2H-pyran-4-yl)(methyl)oxido-λ6-sulfanylidene]-2,2,2-trifluoroacetamide,used as starting material, can be prepared as follows:

a) Sodium hydroxide (50% w/w) (20.04 ml, 379.60 mmol) was added to(3R)-4-(2-chloro-6-(methylsulfinylmethyl)pyrimidin-4-yl)-3-methylmorpholine(2.2 g, 7.59 mmol), 1-bromo-2-(2-bromoethoxy)ethane (3.79 ml, 30.37mmol) and tetraoctylammonium bromide (0.415 g, 0.76 mmol) in methyl THF(20.05 ml). The resulting mixture was stirred at RT for 90 minutes. Thereaction mixture was diluted with methyl THF (50 mL), and washedsequentially with water (50 ml) and saturated brine (5 ml). The organiclayer was dried over MgSO₄, filtered and then evaporated onto silica (30g). The resulting powder was purified by flash chromatography on silica,eluting with a gradient of 0 to 5% MeOH in DCM. Pure fractions wereevaporated to afford(3R)-4-(2-chloro-6-(4-(methylsulfinyl)tetrahydro-2H-pyran-4-yl)pyrimidin-4-yl)-3-methylmorpholine(1.360 g, 50%); ¹H NMR (400 MHz, DMSO-d⁶) 1.84-1.96 (1H, m), 2.02 (1H,td), 2.09 (3H, d), 2.27-2.45 (2H, m), 3.14 (1H, d), 3.10-3.26 (3H, m),3.24 (1H, d), 3.33-3.41 (1H, m), 3.45 (1H, td), 3.60 (1H, dd), 3.71 (1H,d), 3.78-3.87 (1H, m), 3.87-3.97 (2H, m), 4.07 (1H, d), 4.32-4.48 (1H,m), 6.76 (1H, s); m/z: (ES+) MH⁺, 360.11 and 362.06.b) Iodobenzene diacetate (0.788 g, 2.45 mmol) was added to(3R)-4-(2-chloro-6-(4-(methylsulfinyl)tetrahydro-2H-pyran-4-yl)pyrimidin-4-yl)-3-methylmorpholine(0.88 g, 2.45 mmol), magnesium oxide (0.394 g, 9.78 mmol),2,2,2-trifluoroacetamide (0.553 g, 4.89 mmol) and rhodium(II) acetatedimer (0.027 g, 0.06 mmol) in DCM (20 ml). The resulting suspension wasstirred at RT for 18 hours. The reaction mixture was filtered throughCelite and then concentrated in vacuo onto silica (50 g). The resultingpowder was purified by flash chromatography on silica, eluting with agradient of 20 to 60% EtOAc in isohexane. Pure fractions were evaporatedto affordN-[(4-{2-chloro-6-[(3R)-3-methylmorpholin-4-yl]pyrimidin-4-yl}tetrahydro-2H-pyran-4-yl)(methyl)oxido-λ6-sulfanylidene]-2,2,2-trifluoroacetamide(1.018 g, 88%); ¹H NMR (400 MHz, DMSO-d⁶) 1.34 (3H, dd), 2.49 (1H, td),2.63 (2H, ddd), 2.75-2.82 (1H, m), 3.26 (3H, d), 3.29-3.41 (3H, m), 3.49(1H, s), 3.51-3.60 (1H, m), 3.63-3.73 (1H, m), 3.80 (1H, d), 3.98-4.11(4H, m), 6.68 (1H, d); m/z: (ES−) M−H⁻, 469.04 and 471.03.

Example 4.034-{4-[(3R)-3-Methylmorpholin-4-yl]-6-[4-((S)—S-methylsulfonimidoyl)tetrahydro-2H-pyran-4-yl]pyrimidin-2-yl}-1H-indole

A solution ofN-[(4-{2-chloro-6-[(3R)-3-methylmorpholin-4-yl]pyrimidin-4-yl}tetrahydro-2H-pyran-4-yl)(methyl)oxido-λ6-(S)-sulfanylidene]-2,2,2-trifluoroacetamide(50 mg, 0.11 mmol), 1H-indol-4-ylboronic acid (17.09 mg, 0.11 mmol),4,4′-di-tert-butylbiphenyl (5.66 mg, 0.02 mmol) and potassium carbonate(29.3 mg, 0.21 mmol) in degassed DME:water (4:1) (2.5 mL) was added tobis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II)(A-Phos) (7.52 mg, 10.62 μmol) under nitrogen. The resulting mixture wasstirred at RT for 2 hours and then at 55° C. for 20 hours. The reactionmixture was filtered and then purified by preparative HPLC, usingdecreasingly polar mixtures of water (containing 1% NH₃) and MeCN aseluents. Fractions containing product were evaporated to afford thetitle compound (20.80 mg, 43%); ¹H NMR (500 MHz, DMSO-d⁶) 1.28 (3H, d),2.19-2.36 (2H, m), 2.72 (3H, d), 2.84 (2H, t), 3.18 (1H, t), 3.20-3.29(2H, m), 3.56 (1H, td), 3.71 (1H, dd), 3.81 (2H, d), 3.95 (2H, t), 4.03(1H, dd), 4.29 (1H, d), 4.59 (1H, s), 6.87 (1H, d), 7.20 (1H, t), 7.27(1H, t), 7.41-7.49 (1H, m), 7.54 (1H, dd), 8.11 (1H, dd), 11.24 (1H, s);m/z: (ES+) MH⁺, 456.54.

TheN-[(4-{2-chloro-6-[(3R)-3-methylmorpholin-4-yl]pyrimidin-4-yl}tetrahydro-2H-pyran-4-yl)(methyl)oxido-λ6-(S)-sulfanylidene]-2,2,2-trifluoroacetamide,used as starting material, can be prepared as follows:

a) 1-bromo-2-(2-bromoethoxy)ethane (2.323 ml, 18.63 mmol) was added to(R)-4-(2-chloro-6-((S)-methylsulfinylmethyl)pyrimidin-4-yl)-3-methylmorpholine(1.8 g, 6.21 mmol), sodium hydroxide (16.40 ml, 310.58 mmol) andtetraoctylammonium bromide (0.340 g, 0.62 mmol) in methyl THF (12.34ml). The resulting mixture was stirred at RT for 24 hours. The reactionmixture was diluted with methyl THF (50 mL), and then washed with water(100 mL). The organic layer was dried over MgSO₄, filtered andevaporated onto silica (5 g). The resulting powder was purified by flashchromatography on silica, eluting with a gradient of 0 to 5% MeOH inDCM. Pure fractions were evaporated to afford(R)-4-(2-chloro-6-(4-((S)-methylsulfinyl)tetrahydro-2H-pyran-4-yl)pyrimidin-4-yl)-3-methylmorpholine(1.461 g, 65%); ¹H NMR (400 MHz, CDCl₃) 1.34 (3H, d), 1.84-1.94 (1H, m),2.10 (3H, s), 2.24-2.37 (2H, m), 2.44 (1H, ddd), 3.30 (1H, td), 3.41(1H, ddd), 3.51-3.64 (2H, m), 3.65-3.73 (1H, m), 3.75-3.82 (1H, m),3.90-4.08 (4H, m), 4.36 (1H, s), 6.46 (1H, s); m/z: (ES+) MH⁺, 360.15and 362.11.

b) Iodobenzene diacetate (1.437 g, 4.46 mmol) was added to(R)-4-(2-chloro-6-(4-((S)-methylsulfinyl)tetrahydro-2H-pyran-4-yl)pyrimidin-4-yl)-3-methylmorpholine(1.46 g, 4.06 mmol), 2,2,2-trifluoroacetamide (0.459 g, 4.06 mmol),rhodium(II)acetate dimer (0.045 g, 0.10 mmol) and magnesium oxide (0.654g, 16.23 mmol) in DCM (20.29 ml). The resulting suspension was stirredat RT for 48 hours. Further 2,2,2-trifluoroacetamide (0.459 g, 4.06mmol), magnesium oxide (0.654 g, 16.23 mmol), iodobenzene diacetate(1.437 g, 4.46 mmol) and rhodium(II)acetate dimer (0.045 g, 0.10 mmol)were added and the suspension was stirred at RT for a further 24 hours.The reaction mixture was filtered and then evaporated onto silica (5 g).The resulting powder was purified by flash chromatography on silica,eluting with a gradient of 20 to 100% EtOAc in isohexane. Pure fractionswere evaporated to affordN-[(4-{2-chloro-6-[(3R)-3-methylmorpholin-4-yl]pyrimidin-4-yl}tetrahydro-2H-pyran-4-yl)(methyl)oxido-λ6-(S)-sulfanylidene]-2,2,2-trifluoroacetamide(1.421 g, 74%); ¹H NMR (400 MHz, DMSO-d⁶) 1.20 (3H, d), 2.19-2.31 (2H,m), 2.72-2.84 (2H, m), 3.11-3.28 (3H, m), 3.40-3.45 (1H, m), 3.46 (3H,s), 3.53-3.61 (1H, m), 3.74 (1H, d), 3.94 (3H, d), 4.12 (1H, s), 4.47(1H, s), 7.05 (1H, s); m/z: (ES+) MH⁺, 471.04 and 473.00.

Example 5.01 and example 5.024-Fluoro-N-methyl-1-{4-[1-methyl-1-((S)—S-methylsulfonimidoyl)ethyl]-6-[(3R)-3-methylmorpholin-4-yl]pyrimidin-2-yl}-1H-benzimidazol-2-amineand4-fluoro-N-methyl-1-{4-[1-methyl-1-((R)—S-methylsulfonimidoyl)ethyl]-6-[(3R)-3-methylmorpholin-4-yl]pyrimidin-2-yl}-1H-benzimidazol-2-amine

Cesium carbonate (2.74 g, 8.41 mmol) was added to an approximate 4.3:1mixture of R:S isomers ofN-[(2-{2-chloro-6-[(3R)-3-methylmorpholin-4-yl]pyrimidin-4-yl}propan-2-yl)(methyl)oxido-λ6-sulfanylidene]-2,2,2-trifluoroacetamide(0.600 g, 1.40 mmol), sodium methanesulfinate (0.143 g, 1.40 mmol) and7-fluoro-N-methyl-1H-benzo[d]imidazol-2-amine (0.347 g, 2.10 mmol) inDMA (8 ml). The resulting suspension was stirred at 80° C. for 5 hours.The reaction mixture was filtered, diluted with EtOAc (100 ml), andwashed sequentially with water (100 ml), water (100 ml), and saturatedbrine (100 ml). The organic layer was dried over MgSO₄, filtered andthen evaporated. The residue was purified by flash chromatography onsilica, eluting with a gradient of 0 to 5% MeOH in DCM. Pure fractionswere evaporated and the residue purified by preparative chiralchromatography on a Merck 50 mm, 20 μm Chiracel OJ column, elutingisocratically with heptane/(EtOH/MeOH 50/50)/TEA 75/25/0.1 as eluent.The fractions containing product were evaporated to afford the titlecompound:4-fluoro-N-methyl-1-{4-[1-methyl-1-((R)—S-methylsulfonimidoyl)ethyl]-6-[(3R)-3-methylmorpholin-4-yl]pyrimidin-2-yl}-1H-benzimidazol-2-amine(278 mg, 43%) as the first eluting compound; ¹H NMR (400 MHz, DMSO-d⁶)1.30 (3H, d), 1.77 (6H, d), 2.79 (3H, s), 3.05 (3H, d), 3.35 (1H, dd),3.47-3.59 (1H, td), 3.69 (1H, dd), 3.81 (1H, d), 3.93 (1H, s), 4.03 (1H,dd), 4.12 (1H, d), 4.53 (1H, s), 6.83 (1H, s), 6.90-7.01 (2H, m),7.92-7.96 (1H, m), 8.81 (1H, q); m/z: (ES+) MH⁺, 462.53. Chiral HPLC:(Gilson prep, 50 mm 20 μm Chiralcel OJ column eluting withHeptane/(EtOH/MeOH 50/50)/TEA 75/25/0.1) Rf, 10.163 >99%. and4-fluoro-N-methyl-1-{4-[1-methyl-1-((S)—S-methylsulfonimidoyl)ethyl]-6-[(3R)-3-methylmorpholin-4-yl]pyrimidin-2-yl}-1H-benzimidazol-2-amine(96 mg, 15%) as the second eluting compound; ¹H NMR (400 MHz, DMSO-d⁶)1.33 (3H, d), 1.79 (6H, d), 2.83 (3H, s), 3.09 (3H, d), 3.38 (1H, dd),3.59 (1H, td), 3.73 (1H, dd), 3.86 (1H, d), 3.97 (1H, s), 4.06 (1H, dd),4.16 (1H, d), 4.59 (1H, s), 6.88 (1H, s), 6.94-7.05 (2H, m), 7.94-8.02(1H, m), 8.86 (1H, q); m/z: (ES+) MH⁺, 462.53. Chiral HPLC: (Gilsonprep, 50 mm 20 μm Chiralcel OJ column eluting with Heptane/(EtOH/MeOH50/50)/TEA 75/25/0.1) Rf, 14.239 >99%.

TheN-[(2-{2-chloro-6-[(3R)-3-methylmorpholin-4-yl]pyrimidin-4-yl}propan-2-yl)(methyl)oxido-λ6-sulfanylidene]-2,2,2-trifluoroacetamide,used as starting material, was prepared as follows:

a) Methyl iodide (4.70 ml, 75.09 mmol) was added to(R)-4-(2-chloro-6-((R)-methylsulfinylmethyl)pyrimidin-4-yl)-3-methylmorpholine(5.44 g, 18.77 mmol), tetraoctylammonium bromide (1.026 g, 1.88 mmol)and sodium hydroxide (49.6 ml, 938.64 mmol) in methyl THF (110 ml). Theresulting mixture was stirred at RT for 18 hours. The reaction mixturewas diluted with water (250 ml). The organic layer was dried over MgSO₄,filtered and evaporated onto silica gel (10 g). The resulting powder waspurified by flash chromatography on silica, eluting with a gradient of 0to 5% MeOH in DCM. Pure fractions were evaporated to afford(R)-4-(2-chloro-6-(2-((R)-methylsulfinyl)propan-2-yl)pyrimidin-4-yl)-3-methylmorpholine(3.10 g, 52%); ¹H NMR (400 MHz, CDCl₃) 1.32 (3H, t), 1.59 (3H, s), 1.64(3H, s), 2.23 (3H, d), 3.22-3.36 (1H, m), 3.48-3.59 (1H, m), 3.69 (1H,dd), 3.73-3.81 (1H, m), 4.00 (1H, dd), 4.05 (1H, d), 4.31 (1H, s), 6.45(1H, d); m/z: (ES+) MH⁺, 318.02 and 319.98.b) Iodobenzene diacetate (2.77 g, 8.59 mmol) was added to a mixture of(3R)-4-(2-chloro-6-(2-(methylsulfinyl)propan-2-yl)pyrimidin-4-yl)-3-methylmorpholine(1.03 g, 3.24 mmol),(3R)-4-(2-chloro-6-(2-((R)-methylsulfinyl)propan-2-yl)pyrimidin-4-yl)-3-methylmorpholine(1.7 g, 5.35 mmol), magnesium oxide (1.385 g, 34.36 mmol),2,2,2-trifluoroacetamide (1.942 g, 17.18 mmol) and rhodium(II) acetatedimer (0.095 g, 0.21 mmol) in DCM (72 ml). The resulting suspension wasstirred at RT for 70 hours. Further magnesium oxide (0.69 g, 17.18mmol), iodobenzene diacetate (1.38 g, 4.30 mmol),2,2,2-trifluoroacetamide (0.97 g, 8.59 mmol) and rhodium(II) acetatedimer (0.048 g, 0.105 mmol) were added and the mixture was stirred at RTfor 18 hours. The reaction mixture was filtered through Celite and thenconcentrated in vacuo. The residue was purified by flash chromatographyon silica, eluting with a gradient of 20 to 50% EtOAc in heptane. Purefractions were evaporated to afford an approximate 4.3:1 mixture of R:SN-[(2-{2-chloro-6-[(3R)-3-methylmorpholin-4-yl]pyrimidin-4-yl}propan-2-yl)(methyl)oxido-λ6-sulfanylidene]-2,2,2-trifluoroacetamide(1.705 g, 46%); ¹H NMR (400 MHz, DMSO-d⁶) 1.18 (3H, d), 1.83 (6H, s),3.20-3.24 (1H, m), 3.36-3.48 (1H, m), 3.53-3.65 (4H, m), 3.68-3.79 (1H,m), 3.94 (1H, dd), 4.03-4.07 (1H, m), 4.43-4.47 (1H, m), 6.94 (1H, s);m/z: (ES−) M-H—, 427.26.

Example 5.03, Example 5.04, Example 5.05 and Example 5.066-Fluoro-N-methyl-1-{4-[1-methyl-1-((R)—S-methylsulfonimidoyl)ethyl]-6-[(3R)-3-methylmorpholin-4-yl]pyrimidin-2-yl}-1H-benzimidazol-2-amine,5-Fluoro-N-methyl-1-{4-[1-methyl-1-((R)—S-methylsulfonimidoyl)ethyl]-6-[(3R)-3-methylmorpholin-4-ylpyrimidin-2-yl}-1H-benzimidazol-2-amine,5-Fluoro-N-methyl-1-{4-[1-methyl-1-((S)—S-methylsulfonimidoyl)ethyl]-6-[(3R)-3-methylmorpholin-4-yl]pyrimidin-2-yl}-1H-benzimidazol-2-amineand6-fluoro-N-methyl-1-{4-[1-methyl-1-((S)—S-methylsulfonimidoyl)ethyl]-6-[(3R)-3-methylmorpholin-4-yl]pyrimidin-2-yl}-1H-benzimidazol-2-amine

Cesium carbonate (5.01 g, 15.39 mmol) was added to an approximate 4.3:1mixture R:S isomers ofN-[(2-{2-chloro-6-[(3R)-3-methylmorpholin-4-yl]pyrimidin-4-yl}propan-2-yl)(methyl)oxido-λ6-sulfanylidene]-2,2,2-trifluoroacetamide(1.10 g, 2.56 mmol), sodium methanesulfinate (0.262 g, 2.56 mmol) and6-fluoro-N-methyl-1H-benzo[d]imidazol-2-amine (0.720 g, 4.36 mmol) inDMA (16 ml). The resulting suspension was stirred at 80° C. for 5 hours.The reaction mixture was filtered. The reaction mixture was diluted withEtOAc (100 ml), and washed sequentially with water (100 ml), water (100ml), and saturated brine (100 ml). The organic layer was dried overMgSO₄, filtered and then evaporated. The residue was purified by flashchromatography on silica, eluting with a gradient of 0 to 5% MeOH inDCM. Pure fractions were evaporated and the residue was purified bypreparative chiral SFC on a 5 μm Chiracel OJ-H SFC (250 mm×10 mm)column, eluting with CO₂/MeOH+0.5 N,NDMEA 90/10 as eluent. The fractionscontaining product were evaporated to afford the title compound:6-fluoro-N-methyl-1-{4-[1-methyl-1-((R)—S-methylsulfonimidoyl)ethyl]-6-[(3R)-3-methylmorpholin-4-yl]pyrimidin-2-yl}-1H-benzimidazol-2-amine(198 mg, 17%) as the first eluting compound; ¹H NMR (400 MHz, DMSO-d⁶)1.32 (3H, d), 1.77 (6H, d), 2.78 (3H, s), 3.02 (3H, d), 3.33-3.40 (1H,m), 3.55 (1H, td), 3.69 (1H, dd), 3.83 (1H, d), 3.92 (1H, s), 3.97-4.15(2H, m), 4.53 (1H, d), 6.84 (1H, s), 6.91-6.95 (1H, m), 7.21 (1H, dd),7.89 (1H, dd), 8.66 (1H, q); m/z: (ES+) MH⁺, 462.51. Chiral SFC: (BergerMinigram, 5 μm Chiralcel OJ-H (250 mm×4.6 mm) column eluting withCO₂/MeOH/N,NDMEA 90/10/0.5) Rf, 5.56 98.9%. and the title compound:5-fluoro-N-methyl-1-{4-[1-methyl-1-((S)—S-methylsulfonimidoyl)ethyl]-6-[(3R)-3-methylmorpholin-4-yl]pyrimidin-2-yl}-1H-benzimidazol-2-amine(61 mg, 5%) as the fourth eluting compound; ¹H NMR (400 MHz, DMSO-d⁶)1.30 (3H, d), 1.77 (6H, d), 2.78 (3H, s), 3.03 (3H, d), 3.32-3.36 (1H,m), 3.54 (1H, td), 3.68 (1H, dd), 3.81 (1H, d), 3.91 (1H, s), 3.97-4.15(2H, m), 4.53 (1H, d), 6.72-6.84 (2H, m), 7.04 (1H, dd), 8.06 (1H, dd),8.86 (1H, q); m/z: (ES+) MH⁺, 462.53. Chiral SFC: (Berger Minigram, 5 μmChiralcel OJ-H (250 mm×4.6 mm) column eluting with CO₂/MeOH/N,NDMEA90/10/0.5) Rf, 10.29 96.3%.

fractions containing the second and third eluting compounds werepurified by preparative chiral SFC on a 5 μm Chiralcel OD-H (250 mm×4.6mm) column eluting with CO₂/MeOH/N,NDMEA 85/15/0.5 as eluent. Thefractions containing product were evaporated to afford the titlecompound:5-fluoro-N-methyl-1-{4-[1-methyl-1-((R)—S-methylsulfonimidoyl)ethyl]-6-[(3R)-3-methylmorpholin-4-yl]pyrimidin-2-yl}-1H-benzimidazol-2-amine(106 mg, 9%) as the second eluting compound; ¹H NMR (400 MHz, DMSO-d⁶)1.30 (3H, d), 1.76 (6H, d), 2.78 (3H, s), 3.03 (3H, d), 3.31-3.39 (1H,m), 3.54 (1H, td), 3.69 (1H, dd), 3.81 (1H, d), 3.92 (1H, s), 3.97-4.18(2H, m), 4.52 (1H, d), 6.73-6.84 (2H, m), 7.04 (1H, dd), 8.07 (1H, dd),8.86 (1H, q); m/z: (ES+) MH⁺, 462.53. Chiral SFC: (Berger Minigram, 5 μmChiralcel OD-H (250 mm×4.6 mm) column eluting with CO₂/MeOH/N,NDMEA85/15/0.5) Rf, 10.94 98.9%. fractions containing the first elutingcompound were repurified by preparative chiral SFC on a 5 μm ChiralcelOD-H (250 mm×4.6 mm) column eluting with CO₂/MeOH/N,NDMEA 85/15/0.5 aseluent. The fractions containing product were evaporated to afford thetitle compound:6-fluoro-N-methyl-1-{4-[1-methyl-1-((S)—S-methylsulfonimidoyl)ethyl]-6-[(3R)-3-methylmorpholin-4-yl]pyrimidin-2-yl}-1H-benzimidazol-2-amine(12 mg, 1%); ¹H NMR (400 MHz, DMSO-d⁶) 1.14 (3H, d), 1.58 (6H, d), 2.60(3H, s), 2.83 (3H, d), 3.16-3.25 (1H, m), 3.35 (1H, td), 3.50 (1H, dd),3.64 (1H, d), 3.72 (1H, s), 3.79-3.98 (2H, m), 4.34 (1H, d), 6.65 (1H,s), 6.69-6.77 (1H, m), 7.03 (1H, dd), 7.71 (1H, dd), 8.48 (1H, q); m/z:(ES+) MH⁺, 462.53. Chiral SFC: (Berger Minigram, 5 μm Chiralcel OD-H(250 mm×4.6 mm) column eluting with CO₂/MeOH/N,NDMEA 85/15/0.5) Rf, 7.4788.4%.

The 6-fluoro-N-methyl-1H-benzo[d]imidazol-2-amine, used as startingmaterial, can be prepared as follows:

a) 4-Fluorobenzene-1,2-diamine (2 g, 15.86 mmol) was dissolved in THF(49.4 ml) and 1,1′-Carbonyldiimidazole (2.83 g, 17.44 mmol) was added atRT. The reaction mixture was stirred overnight at RT. To this was addedconcentrated ammonia solution (1.5 ml) and the mixture stirred for 30minutes and then diluted with water (100 ml). The resultant solid wascollected by filtration, washed with water, followed by Et₂O and thendried in vacuo to afford 5-fluoro-1H-benzo[d]imidazol-2(3H)-one (1.250g, 52%); ¹H NMR (400 MHz, DMSO-d⁶) 6.66-6.79 (2H, m), 6.81-6.94 (1H, m),10.64 (1H, s), 10.76 (1H, s); m/z: (ES+) MH⁺, 151.19.b) A solution of 5-fluoro-1H-benzo[d]imidazol-2(3H)-one (1.25 g, 8.22mmol) in phosphorus oxychloride (25.2 ml, 270.34 mmol) was heated for 18hours at 100° C. The reaction mixture was cooled to RT and excess ofPOCl₃ was evaporated in vacuo. The residue was neutralized withsaturated NaHCO₃ solution (10 ml) and extracted with EtOAc (3×20 ml).The organic phase was washed with brine and then dried over MgSO₄,filtered and concentrated under reduced pressure to afford2-chloro-6-fluoro-1H-benzo[d]imidazole (1.146 g, 82%); ¹H NMR (400 MHz,DMSO-d⁶) 7.09 (1H, ddd), 7.36 (1H, dd), 7.53 (1H, dd); m/z: (ES+) MH⁺,171.34.c) 2-Chloro-6-fluoro-1H-benzo[d]imidazole (1.146 g, 6.72 mmol) wascharged to high pressure autoclave PV10832 (Parr 160 ml) withmethylamine 40% EtOH solution (50 ml, 6.72 mmol) and sealed on itstrolley and the resulting solution heated to 160° C. in high pressureblast cell 60 for 16 hours. The pressure in the autoclave reached 13bar. The reaction mixture was evaporated and the residue dissolved inMeOH and added to an SCX column. The desired product was eluted from thecolumn using 7M NH₃/MeOH. Fractions containing product were evaporatedand the residue was purified by flash chromatography on silica, elutingwith a gradient of 0 to 10% MeOH in DCM. Pure fractions were evaporatedto afford 6-fluoro-N-methyl-1H-benzo[d]imidazol-2-amine (0.707 g, 64%);¹H NMR (400 MHz, DMSO-d⁶) 2.27 (3H, d), 6.38-6.44 (2H, m), 6.67 (1H,dd), 6.79-6.84 (1H, m); m/z: (ES+) MH⁺, 166.31.

Example 5.07, Example 5.08, Example 5.09 and Example 5.106-Fluoro-N-methyl-1-{4-[(3R)-3-methylmorpholin-4-yl]-6-[1-((R)—S-methylsulfonimidoyl)cyclopropyl]pyrimidin-2-yl}-1H-benzimidazol-2-amineand5-fluoro-N-methyl-1-{4-[(3R)-3-methylmorpholin-4-yl]-6-[1-((R)—S-methylsulfonimidoyl)cyclopropyl]pyrimidin-2-yl}-1H-benzimidazol-2-amineand5-fluoro-N-methyl-1-{4-[(3R)-3-methylmorpholin-4-yl]-6-[1-((S)—S-methylsulfonimidoyl)cyclopropyl]pyrimidin-2-yl}-1H-benzimidazol-2-amineand6-fluoro-N-methyl-1-{4-[(3R)-3-methylmorpholin-4-yl]-6-[1-((S)—S-methylsulfonimidoyl)cyclopropyl]pyrimidin-2-yl}-1H-benzimidazol-2-amine

Cesium carbonate (9.28 g, 28.47 mmol) was added to an approximate 4:1mixture of R:S isomers of(3R)-4-(2-chloro-6-(1-(S-methylsulfonimidoyl)cyclopropyl)pyrimidin-4-yl)-3-methylmorpholine(1.57 g, 4.75 mmol), sodium methanesulfinate (0.484 g, 4.75 mmol) and6-fluoro-N-methyl-1H-benzo[d]imidazol-2-amine (1.332 g, 8.07 mmol) inDMA (23 ml). The resulting suspension was stirred at 80° C. for 5 hours.The reaction mixture was filtered. The reaction mixture was diluted withEtOAc (100 ml), and washed sequentially with water (100 ml), water (100ml), and saturated brine (100 ml). The organic layer was dried overMgSO₄, filtered and evaporated. The residue was purified by flashchromatography on silica, eluting with a gradient of 0 to 5% MeOH inDCM. Pure fractions were evaporated and the residue was then purified bypreparative chiral SFC on a 5 μm Chiralcel OJ-H (20 mm×250 mm) column,using CO₂/MeOH/N,N DMEA 90/10/0.5 as eluent. The fractions containingthe desired compound were evaporated to afford the title compound:6-fluoro-N-methyl-1-{4-[(3R)-3-methylmorpholin-4-yl]-6-[1-((R)—S-methylsulfonimidoyl)cyclopropyl]pyrimidin-2-yl}-1H-benzimidazol-2-amine(225 mg, 10%) as the first eluting compound; ¹H NMR (400 MHz, DMSO-d⁶)1.31 (3H, d), 1.4-1.54 (2H, m), 1.57-1.64 (1H, m), 1.77-1.82 (1H, m),3.00-3.04 (6H, m), 3.33-3.37 (1H, m), 3.53 (1H, td), 3.67 (1H, dd), 3.81(1H, d), 3.93-4.13 (3H, m), 4.49-4.51 (1H, m), 6.80 (1H, s), 6.93 (1H,ddd), 7.22 (1H, dd), 7.87 (1H, dd), 8.64 (1H, q); m/z: (ES+) MH⁺,460.50. Chiral SFC: (Berger Minigram, 5 μm Chiralcel OJ-H (250 mm×4.6mm) column eluting with CO₂/MeOH/N,NDMEA 90/10/0.5) Rf, 7.70 99.9%.

and the title compound:5-fluoro-N-methyl-1-{4-[(3R)-3-methylmorpholin-4-yl]-6-[1-((R)—S-methylsulfonimidoyl)cyclopropyl]pyrimidin-2-yl}-1H-benzimidazol-2-amine(142 mg, 7%) as the second eluting compound; ¹H NMR (400 MHz, DMSO-d⁶)1.50 (3H, d), 1.61-1.77 (2H, m), 1.76-1.89 (1H, m), 1.94-2.06 (1H, m),3.24 (3H, s), 3.27 (3H, d), 3.52-3.56 (1H, m), 3.75 (1H, td), 3.89 (1H,dd), 4.03 (1H, d), 4.15-4.37 (3H, m), 4.70-4.74 (1H, m), 6.94-7.06 (2H,m), 7.27 (1H, dd), 8.28 (1H, dd), 9.07 (1H, q); m/z: (ES+) MH⁺, 460.50.Chiral SFC: (Berger Minigram, 5 μm Chiralcel OJ-H (250 mm×4.6 mm) columneluting with CO₂/MeOH/N,NDMEA 90/10/0.5) Rf, 10.59 99.8%.

and the title compound:6-fluoro-N-methyl-1-{4-[(3R)-3-methylmorpholin-4-yl]-6-[1-((S)—S-methylsulfonimidoyl)cyclopropyl]pyrimidin-2-yl}-1H-benzimidazol-2-amine(36.5 mg, 2%) as the third eluting compound; ¹H NMR (400 MHz, DMSO-d⁶)1.31 (3H, d), 1.44-1.54 (2H, m), 1.57-1.64 (1H, m), 1.77-1.82 (1H, m),3.00-3.04 (6H, m), 3.33-3.37 (1H, m), 3.53 (1H, td), 3.67 (1H, dd), 3.81(1H, d), 3.93-4.13 (3H, m), 4.49-4.51 (1H, m), 6.80 (1H, s), 6.93 (1H,ddd), 7.22 (1H, dd), 7.87 (1H, dd), 8.64 (1H, q); m/z: (ES+) MH⁺,460.50. Chiral SFC: (Berger Minigram, 5 μm Chiralcel OJ-H (250 mm×4.6mm) column eluting with CO₂/MeOH/N,NDMEA 90/10/0.5) Rf, 12.72 97.4%.

and the title compound:5-fluoro-N-methyl-1-{4-[(3R)-3-methylmorpholin-4-yl]-6-[1-((S)—S-methylsulfonimidoyl)cyclopropyl]pyrimidin-2-yl}-1H-benzimidazol-2-amine(80 mg, 4%) as the fourth eluting compound; ¹H NMR (400 MHz, DMSO-d⁶)1.27 (3H, d), 1.43-1.51 (2H, m), 1.55-1.63 (1H, m), 1.72-1.83 (1H, m),3.03 (3H, s), 3.06 (3H, d), 3.28-3.37 (1H, m), 3.52 (1H, td), 3.67 (1H,dd), 3.79 (1H, d), 3.93-4.14 (3H, m), 4.46-4.49 (1H, m), 6.72-6.82 (2H,m), 7.05 (1H, dd), 8.05 (1H, dd), 8.84 (1H, q); m/z: (ES+) MH⁺, 460.50.Chiral SFC: (Berger Minigram, 5 μm Chiralcel OJ-H (250 mm×4.6 mm) columneluting with CO₂/MeOH/N,NDMEA 90/10/0.5) Rf, 25.03 99.5%.

The 4:1 mixture of R:S isomers of(3R)-4-(2-chloro-6-(1-(S-methylsulfonimidoyl)cyclopropyl)pyrimidin-4-yl)-3-methylmorpholine,used as starting material, was prepared as follows:

Sodium hydroxide (50%, 80 ml, 1496.99 mmol) was added to an approximate4:1 mixture of R:S isomers of(3R)-4-(2-chloro-6-(S-methylsulfonimidoylmethyl)pyrimidin-4-yl)-3-methylmorpholine(10 g, 24.95 mmol), 1,2-dibromoethane (8.60 ml, 99.80 mmol) andtetraoctylammonium bromide (1.364 g, 2.49 mmol) in methyl THF (500 ml)at 20° C. under nitrogen. The resulting mixture was stirred at 20° C.for 24 hours. The reaction mixture was diluted with methyl THF (500 ml)and the aqueous layer separated. The mixture was diluted further withEtOAc (1000 ml) and washed with water (1500 ml). The organic layer wasdried over MgSO₄, filtered and evaporated. The residue was purified byflash chromatography on silica, eluting with a gradient of 0 to 5% MeOHin DCM. Pure fractions were evaporated to dryness to afford anapproximate 4:1 mixture of R:S isomers of(3R)-4-(2-chloro-6-(1-(S-methylsulfonimidoyl)cyclopropyl)pyrimidin-4-yl)-3-methylmorpholine(1.570 g, 19%); ¹H NMR (400 MHz, DMSO-d⁶) 1.18 (3H, d), 1.25-1.50 (3H,m), 1.59-1.71 (1H, m), 3.01 (3H, s), 3.19 (1H, t), 3.39-3.46 (1H, m),3.52-3.61 (1H, m), 3.72 (1H, d), 3.86 (1H, s), 3.93 (1H, dd), 4.01-4.05(1H, m), 4.38 (1H, s), 6.95 (1H, s); m/z: (ES+) MH⁺, 331.39.

1. A compound of formula (I):

wherein: R¹ is selected from morpholin-4-yl and 3-methylmorpholin-4-yl;R² is

n is 0 or 1; R^(2A), R^(2C), R^(2E) and R^(2F) each independently arehydrogen or methyl; R^(2B) and R^(2D) each independently are hydrogen ormethyl; R^(2G) is selected from —NHR⁷ and —NHCOR⁸; R²H is fluoro; R³ ismethyl; R⁴ and R⁵ are each independently hydrogen or methyl, or R⁴ andR⁵ together with the atom to which they are attached form Ring A; Ring Ais a C₃₋₆cycloalkyl or a saturated 4-6 membered heterocyclic ringcontaining one heteroatom selected from O and N; R⁶ is hydrogen; R⁷ ishydrogen or methyl; R⁸ is methyl, or a pharmaceutically acceptable saltthereof.
 2. A compound according to claim 1 wherein R⁴ and R⁵ togetherwith the atom to which they are attached form Ring A, and Ring A is aC₃₋₆cycloalkyl or a saturated 4-6 heterocyclic ring containing oneheteroatom selected from O and N.
 3. A compound according to claim 1wherein Ring A is a cyclopropyl, tetrahydropyranyl or piperidinyl ring.4. A compound according claim 1 wherein R^(2A) is hydrogen; R^(2B) ishydrogen; R^(2C) is hydrogen; R^(2D) is hydrogen; R^(2E) is hydrogen;and R^(2F) is hydrogen.
 5. A compound according to claim 1 wherein R¹ is3-methylmorpholin-4-yl.
 6. A compound according to claim 4 wherein R¹ is3-methylmorpholin-4-yl.
 7. A compound according to claim 1 where thecompound of formula (I) is a compound of formula (Ia),

or a pharmaceutically acceptable salt thereof.
 8. A compound accordingto claim 7, or a pharmaceutically acceptable salt, thereof wherein: RingA is cyclopropyl ring; R² is

n is 0 or 1; R^(2A) is hydrogen; R^(2B) is hydrogen; R^(2C) is hydrogen;R^(2D) is hydrogen; R^(2E) is hydrogen; R^(2F) is hydrogen; R^(2G) is—NHR⁷; R^(2H) is fluoro; R³ is a methyl group; R⁶ is hydrogen; and R⁷ ishydrogen or methyl, or a pharmaceutically acceptable salt thereof.
 9. Acompound according to claim 1 wherein the compound of formula (I) isselected from any one of4-{4-[(3R)-3-Methylmorpholin-4-yl]-6-[((R)—S-methylsulfonimidoyl)methyl]pyrimidin-2-yl}-1H-pyrrolo[2,3-b]pyridine;4-{4-[(3R)-3-Methylmorpholin-4-yl]-6-[1-((S)—S-methylsulfonimidoyl)cyclopropyl]pyrimidin-2-yl}-1H-pyrrolo[2,3-b]pyridine;4-{4-[(3R)-3-Methylmorpholin-4-yl]-6-[1-((R)—S-methylsulfonimidoyl)cyclopropyl]pyrimidin-2-yl}-1H-pyrrolo[2,3-b]pyridine;N-Methyl-1-{4-[(3R)-3-methylmorpholin-4-yl]-6-[1-((R)—S-methylsulfonimidoyl)cyclopropyl]pyrimidin-2-yl}-1H-benzimidazol-2-amine;N-Methyl-1-{4-[(3R)-3-methylmorpholin-4-yl]-6-[1-((S)—S-methylsulfonimidoyl)cyclopropyl]pyrimidin-2-yl}-1H-benzimidazol-2-amine;4-{4-[(3R)-3-Methylmorpholin-4-yl]-6-[1-((R)—S-methylsulfonimidoyl)cyclopropyl]pyrimidin-2-yl}-1H-indole;4-{4-[(3R)-3-methylmorpholin-4-yl]-6-[1-((S)—S-methylsulfonimidoyl)cyclopropyl]pyrimidin-2-yl}-1H-indole;1-{4-[(3R)-3-Methylmorpholin-4-yl]-6-[1-((R)—S-methylsulfonimidoyl)cyclopropyl]pyrimidin-2-yl}-1H-benzimidazol-2-amine;1-{4-[(3R)-3-methylmorpholin-4-yl]-6-[1-((S)—S-methylsulfonimidoyl)cyclopropyl]pyrimidin-2-yl}-1H-benzimidazol-2-amine;4-Fluoro-N-methyl-1-{4-[(3R)-3-methylmorpholin-4-yl]-6-[1-((R)—S-methylsulfonimidoyl)cyclopropyl]pyrimidin-2-yl}-1H-benzimidazol-2-amine;4-fluoro-N-methyl-1-{4-[(3R)-3-methylmorpholin-4-yl]-6-[1-((S)—S-methylsulfonimidoyl)cyclopropyl]pyrimidin-2-yl}-1H-benzimidazol-2-amine;4-{4-[(3R)-3-Methylmorpholin-4-yl]-6-[1-(S-methylsulfonimidoyl)cyclopropyl]pyrimidin-2-yl}-1H-pyrrolo[2,3-c]pyridine;N-methyl-1-{4-[1-methyl-1-((S)—S-methylsulfonimidoyl)ethyl]-6-[(3R)-3-methylmorpholin-4-yl]pyrimidin-2-yl}-1H-benzimidazol-2-amine;N-methyl-1-{4-[1-methyl-1-((R)—S-methylsulfonimidoyl)ethyl]-6-[(3R)-3-methylmorpholin-4-yl]pyrimidin-2-yl}-1H-benzimidazol-2-amine;N-Methyl-1-{4-[(3R)-3-methylmorpholin-4-yl]-6-[4-((S)—S-methylsulfonimidoyl)tetrahydro-2H-pyran-4-yl]pyrimidin-2-yl}-1H-benzimidazol-2-amine;N-methyl-1-{4-[(3R)-3-methylmorpholin-4-yl]-6-[4-((R)—S-methylsulfonimidoyl)tetrahydro-2H-pyran-4-yl]pyrimidin-2-yl}-1H-benzimidazol-2-amine;4-{4-[(3R)-3-Methylmorpholin-4-yl]-6-[4-((S)—S-methylsulfonimidoyl)tetrahydro-2H-pyran-4-yl]pyrimidin-2-yl}-1H-indole;4-Fluoro-N-methyl-1-{4-[1-methyl-1-((S)—S-methylsulfonimidoyl)ethyl]-6-[(3R)-3-methylmorpholin-4-yl]pyrimidin-2-yl}-1H-benzimidazol-2-amine;4-fluoro-N-methyl-1-{4-[1-methyl-1-((R)—S-methylsulfonimidoyl)ethyl]-6-[(3R)-3-methylmorpholin-4-yl]pyrimidin-2-yl}-1H-benzimidazol-2-amine;6-Fluoro-N-methyl-1-{4-[1-methyl-1-((R)—S-methylsulfonimidoyl)ethyl]-6-[(3R)-3-methylmorpholin-4-yl]pyrimidin-2-yl}-1H-benzimidazol-2-amine;5-Fluoro-N-methyl-1-{4-[1-methyl-1-((R)—S-methylsulfonimidoyl)ethyl]-6-[(3R)-3-methylmorpholin-4-yl]pyrimidin-2-yl}-1H-benzimidazol-2-amine;5-Fluoro-N-methyl-1-{4-[1-methyl-1-((S)—S-methylsulfonimidoyl)ethyl]-6-[(3R)-3-methylmorpholin-4-yl]pyrimidin-2-yl}-1H-benzimidazol-2-amine;6-fluoro-N-methyl-1-{4-[1-methyl-1-((S)—S-methylsulfonimidoyl)ethyl]-6-[(3R)-3-methylmorpholin-4-yl]pyrimidin-2-yl}-1H-benzimidazol-2-amine;6-Fluoro-N-methyl-1-{4-[(3R)-3-methylmorpholin-4-yl]-6-[1-((R)—S-methylsulfonimidoyl)cyclopropyl]pyrimidin-2-yl}-1H-benzimidazol-2-amine;5-fluoro-N-methyl-1-{4-[(3R)-3-methylmorpholin-4-yl]-6-[1-((R)—S-methylsulfonimidoyl)cyclopropyl]pyrimidin-2-yl}-1H-benzimidazol-2-amine;5-fluoro-N-methyl-1-{4-[(3R)-3-methylmorpholin-4-yl]-6-[1-((S)—S-methylsulfonimidoyl)cyclopropyl]pyrimidin-2-yl}-1H-benzimidazol-2-amine;and6-fluoro-N-methyl-1-{4-[(3R)-3-methylmorpholin-4-yl]-6-[1-((S)—S-methylsulfonimidoyl)cyclopropyl]pyrimidin-2-yl}-1H-benzimidazol-2-amine,or a pharmaceutically acceptable salt thereof.
 10. A pharmaceuticalcomposition comprising a compound of formula (I), or a pharmaceuticallyacceptable salt thereof, according to claim 1 in association with apharmaceutically acceptable adjuvant, diluent or carrier.
 11. A methodfor treating cancer which comprises administering to a patient in needthereof a therapeutically effective amount of a compound of formula (I),or a pharmaceutically acceptable salt thereof, according to claim
 1. 12.A method for treating cancer which comprises administering to a patientin need thereof a therapeutically effective amount of a compound offormula (I), or a pharmaceutically acceptable salt thereof, according toclaim 9.